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Steven O. Smith Ph.D.

Director of Structural Biology
Department of Biochemistry and Cell Biology

Center for Structural Biology
138 Centers for Molecular Medicine
Stony Brook University
Stony Brook, NY 11794-5215

Office telephone: 631-632-1210
Lab telephone: 631-632-1212
Fax: 631-632-8575


  • Research Description
    G Protein-Coupled Receptors

    G protein-coupled receptors (GPCRs) are largest family of membrane receptor protein and the target of most pharmaceuticals made today. The first step in the activation mechanism of most GPCRs is the binding of a signaling ligand. Ligand binding to the extracellular loops or within the transmembrane helical bundle of these receptors leads to an allosteric conformational change that promotes G protein activation. The precise location of the activating ligand and the conformational changes triggered by ligand binding are unknown for any GPCR.

    Our research on signal transduction mechanisms mediated by GPCRs mainly involves the visual pigment rhodopsin. Rhodopsin is the receptor in vertebrate rod cells responsible for vision in dim light. However, we have recently begun structural studies on CCR5, a chemokine receptor in T-cells, and the b 2-adrenoreceptor. The b 2-adrenoreceptor mediates physiological responses to adrenaline and noradrenaline, and plays a critical role in the regulation of the cardiovascular system.

    The structure of rhodopsin consists of a bundle of seven transmembrane helices that surround the photoreactive chromophore, 11-cis retinal. Absorption of a single photon of light is sufficient to isomerize the retinal from cis to trans, and activate the protein. Using solid-state NMR spectroscopy, we can define the position of the retinal in the active and inactive states of rhodopsin, and the structural changes within the retinal binding site that lead to receptor activation. The location of the retinal in activated rhodopsin and its interaction with sequence motifs that are highly conserved across the pharmaceutically important class A GPCR family has provided the basis for a general mechanism of GPCR activation.

    Amyloid Fibril Structure, Formation and Inhibition

    Amyloid assemblies are found in many neurodegenerative pathologies including Alzheimer’s, Huntington’s, and prion diseases. Although much is known about the physiological consequences of these assemblies, very little is known about the high resolution structures of these b -sheet rich fibrils and their oligomeric precursors. A combination of several biophysical methodologies including solid-state NMR, infrared spectroscopy, fluorescence assays, electron microscopy, and atomic force microscopy are being used to obtain high resolution structural information of these multimeric complexes. The data obtained is being used to design novel peptide and small molecule inhibitors to disrupt the formation of these assemblies and reduce their toxicity to cultured neurons.

    Cytokine Receptors

    Cytokine receptors are a family of transmembrane proteins that include the erythropoietin receptor and the thrombopoietin receptor, among others. These proteins bind ligand (hormones) through an extracellular domain, transmitting a signal through the membrane that results in intracellular effects that include inhibition of apoptosis and usually mitogenesis. Though it is known that these effects are mediated by receptor dimerization and the Jak/STAT pathway, the precise mechanism by which these tasks are accomplished remains elusive.

    Erythropoietin (Epo) stimulates erythropoiesis in hematopoietic stem cells. It does this by binding to the extracellular domain of the erythropoietin receptor, transmitting a signal through the transmembrane domain to the intracellular domain, resulting in activation of the Jak/STAT pathway and production of red blood cells. It has been shown that the Epo receptor exists as preformed dimers, though the point of monomer association is a hotly contested issue. We believe that dimerization is mediated through the TM domain that locks the receptor in an “off” position in the absence of ligand. Epo binding results in a change in TM domain conformation that somehow allows Jak2 to phosphorylate the cytoplasmic tyrosine residues on the receptor and other Jak2 molecules. This results in stimulation of mitogenesis and production of red blood cells.

    While many groups have studied functional receptor mutants and a crystal structure of the extracellular domain exists, the complete structure remains to be solved. Using recombinantly expressed protein constructs and solution NMR spectroscopy, we aim to solve the complete structure of the Epo receptor and propose a model of receptor activation that may extend to other members of the hematopoietin receptor family. Insights into the structure-function of the Epo receptor may provide a general model for the activation of other cytokine receptors and could facilitate the development of pharmacotherapies for the treatment of erythropoietic diseases.

    Basic – Aromatic Clusters in Peripheral Membrane Proteins  

    Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 or PIP2) has emerged as a key regulator of signal transduction in cell membranes. Hydrolysis of PI(4,5)P 2 by phospholipase C generates two important second messengers, inositol triphosphate (IP 3 ) and diacylglycerol (DAG). Phosphorylation of PI(4,5)P 2 by PI-3 kinase generates another second messenger, PI(3,4,5)P 3 . In addition, PI(4,5)P 3 itself plays a crucial role in many different cellular processes including membrane trafficking and transport, exocytosis and endocytosis, and cytoskeletal attachment.

    We are interested in how the concentration of PIP2 is regulated in cell membranes so that it can carry out its many functions in a coordinated fashion. One mechanism of regulation is by MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate protein), a membrane-associated protein that participates in many cell signaling pathways. MARCKS is able to sequester PIP2 in lateral membrane domains when its highly positively charged effector domain (151-175) is not phosphorylated. Phosphorylation by PKC releases the effector domain from the membrane surface , which in turn frees locally sequestered PIP2. We are in the process of determining the structure of the membrane bound effector domain of MARCKS and how it interacts with PI(4,5)P 2 .

    Ion Channels

    We are also interested in the mechanism of gating and selectivity in ion channels. Research in our lab is focused on the structure and function of phospholamban, a 52-residue ion channel protein found in cardiac muscle cells that regulates calcium levels across the sarcoplasmic reticulum membrane.

    Phospholamban is essential in b -adrenergic response in the heart. During muscle contraction, phospholamban binds to the Ca 2+ pump and prevents Ca 2+ from being pumped back into the SR. During muscle relaxation, phospholamban is phosphorylated by Protein Kinase A at Ser16 and Thr17 which removes the inhibition and restores low calcium levels in the cytoplasm. Though the 52-residue peptide is most inhibitory as a monomer, phospholamban also associates into pentamers that have been shown to be selective for Ca 2+ ions.

    The structure of phospholamban is central to its function. We are using various biochemical and biophysical methods to investigate the structure and function of this peptide and to understand its mechanism. We are able to determine its global secondary structure by CD and FTIR spectroscopy, and full three dimensional structure by solid state NMR.

    Membrane Protein Folding and Structure

    Membrane proteins commonly fold into bundles of helices, and helix interactions are important for their folding, stability and function. However, the nature and distribution of the amino acids in membrane proteins is very different than in soluble proteins. The difference in the composition of the surface-exposed residues is well known and simply reflects the environment of the protein, i.e. in soluble proteins polar and charged residues are on the water-accessible surface, whereas in membrane proteins hydrophobic residues cover the lipid-exposed surface. Much less is known about the nature and distribution of amino acids in the interiors of membrane and soluble proteins.

    Combining structural studies of membrane proteins with bioinformatics approaches, we have shown that both helical membrane and soluble proteins make use of a general motif for helix interactions which relies mainly on four residues (Leu, Ala, Ile, Val) to mediate helix interactions in a fashion characteristic of left-handed helical coiled-coils. However, a second ‘motif’ for mediating helix interactions is revealed by the high occurrence and high average packing values of small and polar amino acids (Ala, Gly, Ser, Thr) in the helix interfaces of membrane proteins. There is a strong linear correlation between the occurrence of residues in helix-helix interfaces and their packing values. Based on this correlation, we introduced the concept of a helix packing moment to predict the orientation of helices in helical membrane proteins and membrane protein complexes. The helix packing moment is a complementary tool to the helical hydrophobic moment in the analysis of transmembrane sequences. Helix packing moments also help to identify the packing interfaces in membrane proteins with multiple transmembrane helices, where a single helix can have multiple contact surfaces.

    Analyses on class A G protein-coupled receptors (GPCRs) with 7 transmembrane helices show that helix packing moments are conserved across the class A family of GPCRs and correspond to key structural contacts in rhodopsin. These contacts are distinct from the highly conserved signature motifs of GPCRs and have not previously been recognized. The specific amino acid types involved in these contacts, however, are not necessarily conserved between subfamilies of GPCRs, indicating that the same protein architecture can be supported by a diverse set of interactions. In GPCRs, as well as membrane channels and transporters, amino acids with small side chains ( Gly, Ala, Ser, Cys) allow tight helix packing by mediating strong van der Waals interactions between helices. Closely packed helices, in turn, facilitate interhelical hydrogen bonding of both weakly polar (Ser, Thr, Cys) and strongly polar (Asn, Gln, Glu, Asp, His, Arg, Lys) amino acids.

  • Publications
    1. Defour JP, Levy G, Leroy E, Smith SO, Constantinescu SN (2019). The S505A thrombopoietin receptor mutation in childhood hereditary thrombocytosis and essential thrombocythemia is S505N: single letter amino acid code matters.  Leukemia, doi: 10.1038/s41375-018-0356-x.
    1. Chung H, Crooks EJ, Ziliox M, Smith SO. (2018) Disaggregation of Aβ42 for structural and biochemical studies.  Methods Mol Biol. 1777:321-330.
    2. Davis J, Xu F, Hatfield J, Lee H, Hoos MD, Popescu D, Crooks E, Kim R, Smith SO, Robinson JK, Benveniste H, Van Nostrand WE. (2018) A novel transgenic rat model of robust cerebral microvascular amyloid with prominent vasculopathy.   Am J Pathol. 188: 2877-2889.
    1. Hu Y, Kienlen-Campard P, Tang TC, Perrin F, Opsomer R, Decock M, Pan X, Octave JN, Constantinescu SN, Smith SO  (2017) β-Sheet structure within the extracellular domain of C99 regulates amyloidogenic processing.  Scientific Reports. 7(1):17159.
    2. Sanchez-Reyes OB, Cooke ALG, Tranter DB, Rashid D, Eilers M, Reeves PJ, Smith SO. (2017) G protein-coupled receptors contain two conserved packing clusters.  Biophys J.  112(11): 2315-2326.
    1. Leroy, E., Defour, J.P., Sato, T., Dass, S., Gryshkova, V, Shwe, M.M., Staerk, J., Constantinescu, S.N. and Smith, S.O. (2016) His499 regulates dimerization and prevents oncogenic activation by asparagine mutations of the human thrombopoietin receptor. J. Biol. Chem. 291, 2974-87.
    2. Decock, M., Stanga, S., Octave, J.-N., Dewachter, I., Smith, S.O., Constantinescu, S.N., and Kienlen-Campard, P. (2016) Glycines from the APP GXXXG/GXXXA transmembrane motifs promote formation of pathogenic Aβ oligomers in cells. Frontiers in Aging Neuroscience. 8:107
    3. Kimata N, Pope A, Eilers M, Opefi CA, Ziliox M, Hirshfeld A, Zaitseva E, Vogel R, Sheves M, Reeves PJ, and Smith S.O. (2016) Retinal orientation and interactions in rhodopsin reveal a two stage trigger mechanism for activation. Nature Communications 7, 12683.
    4. Kimata N, Pope A, Sanchez-Reyes, O.B., Eilers M, Opefi CA, Ziliox M, Reeves PJ, and Smith S.O. (2016) Free backbone carbonyls mediate rhodopsin activation. Nature Struct Mol Biol. 2016 Aug;23(8):738-43.
    5. Xu, F., Fu, Z., Dass, S., Kotarba, A.E., Davis, J., Smith, S.O. & Van Nostrand, W.E. (2016) Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure. Nature Commun. 7, 13527.
    1. Fu Z, Aucoin D, Davis J, Van Nostrand WE and Smith SO. (2015) Mechanism of Nucleated Conformational Conversion of Aβ42.  Biochemistry 54(27):4197-207.
    2. Opefi CA, Tranter D, Smith SO, and Reeves PJ. (2015) Construction of stable mammalian cell lines for inducible expression of G protein-coupled receptors. Methods Enzymol. 556:283-305.
    3. Kimata N, Reeves PJ, and Smith SO. (2015) Uncovering the triggers for GPCR activation using solid-state NMR spectroscopy. J Magn Reson.  253:111-8.
    4. Kimata N, Pope A, Rashid D, Reeves PJ, Smith SO. (2015) Sequential structural changes in rhodopsin occurring upon photoactivation. Methods Mol Biol. 1271:159-71.
    5. Marinangeli C, Tasiaux B, Opsomer R, Hage S, Sodero AO, Dewachter I, Octave JN, Smith SO, Constantinescu SN, and Kienlen-Campard P (2015) Presenilin transmembrane domain 8 conserved AXXXAXXXG motifs are required for the activity of the γ-secretase complex.  J Biol Chem. 290(11):7169-84.
    6. Decock M, El Haylani L, Stanga S, Dewachter I, Octave JN, Smith SO, Constantinescu SN, Kienlen-Campard P. (2015) Analysis by a highly sensitive split luciferase assay of the regions involved in APP dimerization and its impact on processing.  FEBS Open Bio 5, 763-773.
    1. Pope, A, Eilers, M., Reeves, P., and Smith, S.O. (2014) Amino acid conservation and interactions in rhodopsin:  Probing receptor activation by NMR spectroscopy.  Biochim. Biophys. Acta, 1837(5):683-93.
    2. Tang, T.C., Hu, Y., Kienlen-Campard, P., El-Haylani, L., Van Hees, J., Fu, Z., Octave, J.-N., Constantinescu, S.N., and Smith, S.O. (2014)  Conformational changes induced by the A21G Flemish mutation in the amyloid precursor protein lead to increased Ab production.  Structure 2014 Mar 4;22(3):387-9
    3. Xu, F., Kortarba, A.E., Fu, Z., Davis, J., Smith, S.O., and Van Nostrand, W. (2014) Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice, J. Biol. Chem, 289(25):17895-908.
    4. Tamagaki H, Furukawa Y, Yamaguchi R, Hojo H, Aimoto S, Smith SO, Sato T.  (2014) Coupling of transmembrane helix orientation to membrane release of the juxtamembrane region in FGRF3. Biochemistry 53(30):5000-7.
    5. Fu Z, Aucoin D, Ahmed M, Ziliox M, Van Nostrand WE, Smith SO. (2014) Capping of Aß42 oligomers by small molecule inhibitors. Biochemistry 53(50):7893-903.
    1. Matsushita, C., Tamagaki, H., Miyazawa, Y., Aimoto, S., Smith, S.O. and Sato, T. (2013) Transmembrane helix orientation influences membrane binding of the intracellular juxtamembrane domain in Neu receptor peptides. Proc. Natl. Acad. Sci. USA 110:1646-51.
    2. Defour, J.P., Itaya, M., Gryshkova, V., Brett, I.C., Pecquet, C., Sato, T., Smith, S.O., and Constantinescu, S.A. (2013) A tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation. Proc. Natl. Acad. Sci. USA, 110:2540-5
    3. Kotarba AE, Aucoin D, Hoos MD, Smith SO, Van Nostrand WE. (2013) Fine mapping of the< amyloid β-protein binding site on myelin basic protein. Biochemistry. 2013 52(15): 2565-73.
    4. Opefi, C.A., South, K., Reynolds, C., Smith, S.O. and Reeves, P.J. (2013) Retinitis pigmentosa mutants provide insight into the role of the N-terminal cap in rhodopsin folding, structure, and function, J. Biol. Chem 288:33912-26.
    5. Xu, B., Chakrabory, R., Eilers, M., Dakshinamurti, S., O’Neil, J.D., Smith, S.O., Bhullar, R.P., and Chelikani, P. (2013) High level expression, purification and characterization of a constitutively active thromboxane A2 receptor polymorphic variant. PLoS ONE, 8(9):e76481.
    6. Lin C.P., Kim C., Smith S.O. and Neiman A.M. (2013) A highly redundant gene network controls assembly of the outer spore wall in S. cerevisiae. PLoS Genetics, 9(8):e1003700.
    1. Eilers, M., Goncalves, J., Ahuja, S., Kirkup, C, Hirshfeld, A, Simmerling, C., Reeves, P.J., Sheves, M and Smith, S.O. (2012) Structural transitions of transmembrane helix 6 in the formation of metarhodopsin I. J. Phys. Chem, 116: 10477-10489.
    2. Ladiwala A.R, Litt J., Kane R.S., Aucoin D.S., Smith S.O., Ranjan S., Davis J., Van Nostrand W.E., Tessier P.M. (2012) Conformational differences between two amyloid b oligomers of similar size and dissimilar toxicity. J Biol Chem. 287: 24765-24773.
    1. Arakawa M., Chakraborty R., Upadhyaya J., Eilers M., Reeves P.J., Smith S.O. and Chelikani, P. (2011) Structural and functional roles of small group-conserved amino acids present on helix-H7 in the β2-adrenergic receptor. Biochim Biophys Acta. 1808: 1170-1178.
    2. Staerk, J., Defour, J.-P., Pecquet, C., Leroy, E., Antoine-Poirel, H., Brett, I., Itaya, M., Smith, S.O., Vainchenker, W. and Constantinescu, S.N. (2011) Orientation-specific signaling by thrombopoietin receptor dimers, EMBO J. 30(21):4398-413.
    1. Smith, S.O. (2010) Structure and activation mechanism of the visual pigment rhodopsin. Annual Reviews of Biophysics. 9, 309-328.
    2. Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliott, J.I., Van Nostrand W.E. and Smith, S.O. (2010) Structural conversion of neurotoxic Aβ42 oligomers to fibrils. Nature Struct. Molec. Biology, 17:561-567.
    3. Khalifa, N.K, Van Hees, J., Tasiaux, B., Huysseune, S., Smith, S.O., Constantinescu, S.N., Octave, J.-N. and Kienlen-Campard, P. (2010) What is the role of amyloid precursor protein dimerization? Cell Adhesion and Migration, 4, 268-272. PMC Journal - In Process
    4. Goncalves, J., Ahuja, S., Erfani, S., Eilers, M. and Smith, S.O. (2010) Structure and function of G protein coupled receptors using NMR spectroscopy. Prog. NMR Spectroscopy 57, 159- 180. PMC 217457
    5. Goncalves, J., South, K., Ahuja, S., Zaitseva, E., Opefi, C.A., Eilers, M., Vogel, R., Reeves, P.J. and Smith, S.O. (2010) Highly conserved tyrosine stabilizes the active state of rhodopsin. Proc. Natl. Acad. Sci. USA, 107: 19861-19866.
    6. Liao, M.-C., Hoos, M.D., Aucoin, D., Ahmed, M., Davis, J., Smith, S.O. and Van Nostrand, W. (2010) Amino terminal domain of myelin basic protein inhibits amyloid β -protein fibril assembly. J. Biol. Chem., 285: 35590-35598
    1. Aucoin, D., Camenares, D., Zhao, X., Jung, J., Sato T. and Smith, S.O. resolution 1H MAS RFDR NMR of biological membranes. J. Magn. Reson. Mar;197(1):77-86.
    2. Sato, T., Tang, T., Reubins, G., Fei, J. Z., Fujimoto, T., Kienlen-Campard, P., Constantinescu, S.N., Octave, J. N., Aimoto, S. and Smith, S.O. Cut Site in the Transmembrane Dimer of the Amyloid Precursor Protein is Required for Proteolysis. (2009) Proc. Natl. Acad. Sci. 106(5):1421-6.
    3. Ahuja, S., Hornak, V., Yan, E. C. Y., Syrett, N., Goncalves, J., Hirshfeld, A., Ziliox, M., Sakmar, T.P., Sheves, M., Reeves, P.J., Smith, S.O. coupled to displacement of the second extracellular loop 2 in rhodopsin activation. Nature Struct. Molec. Biology 16:168-75.
    4. Ahuja, S., Crocker, E., Eilers, M., Hornak, V., Syrett, N., Reeves, P.J., Khorana, H.G., Sheves, M. and Smith, S.O.
        1. visual pigment rhodopsin. J. Biol. Chem. 284(15):10190-201
    5. Sengupta, P., Bosis, E., Nachliel, E., Gutman, M., Smith, S.O., Mihályné, G., Zaitseva, I., McLaughlin, S. (2009) EGFR juxtamembrane domain, membranes and calmodulin: kinetics of their interaction. Biophys. J. Biophys J. 2009 Jun 17;96(12):4887-95.
    6. Hoos, M. D., Ahmed, M., Smith, S.O., and Van Nostrand, W.E. (2009) Myelin basic protein binds to and inhibits the fibrillar assembly of Aβ42 in-vitro. Biochemistry, Jun 9;48(22):4720- 7.
    7. Liao, M.C., Ahmed, M., Smith, S.O. and Van Nostrand W.E. (2009) Degradation of amyloid beta protein by purified myelin basic protein. J. Biol Chem. 284: 28917-25
    8. Hornak, V., Ahuja, S., Eilers, M., Reeves, P, Sheves, M. and Smith, S.O. (2010) A view of the activated state of rhodopsin from guided molecular dynamics simulations. J. Mol. Biol. 396, 510–527.
    9. Ahuja, S., Eilers, M., Hirshfeld, A., Yan, E.C.Y., Ziliox, M., Sakmar, T.P., Sheves, M. and Smith., S.O. (2009) 6-s-cis conformation and polar binding pocket of the retinal chromophore in the photoactivated state of rhodopsin. J. Am. Chem. Soc. 131(42):15160-9.
    10. Ahuja, S. and Smith, S.O. (2009) Multiple switches in G protein-coupled receptor activation. Trends Pharm Sci. 30(9):494-502 (2009) A Helix-to-Coil Transition at the ε- and Eilers, M. (2009) Helix movement is (2009) Location of the retinal chromophore in the activated state of the
    11. Plo, I., Zhang, Y., Le Couédic, J.P., Nakatake, M., Boulet, J.M., Itaya, M., Smith, S.O., Debili, N., Constantinescu, S.N., Vainchenker, W., Louache, F. and de Botton, S. (2009) An activating mutation in the CSF3R receptor gene induces a hereditary chronic neutrophilia. J. Exp. Med. 206(8):1701-7.
    12. Konno, H., Aimoto, S. Smith, S.O. Nosaka, K. and Akaji, K. (2009) Synthesis of [19, 35, 36- 13C3]-labeled TAK779 as a molecular probe. Bioorg. Med. Chem. 7(16):5769-74.
    1. Kienlen-Campard, P., Tasiaux, B., Van Hees, J., Li, M., Huysseune, S., Sato, T., Fei, J., Aimoto, S., Courtoy, P.J., Smith, S.O. Constantinescu, S.N., and Octave, J. N. (2008) Amyloidogenic processing but not AICD production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs. J. Biol. Chem., 283, 7733-7744.
    1. Hoos, M., Ahmed, M., Smith, S. O. and van Nostrand, W. (2007) Inhibition of familial cerebral amyloid angiopathy mutant amyloid β-protein fibril assembly by myelin basic protein. J. Biol. Chem. 30, 9952-61.
    2. Chelikani, P., Hornak, V., Eilers, M., Reeves, P. J., RajBhandary, U. L., Smith, S. O. and Khorana, H. G., (2007) Helix-helix interactions in the β-adrenergic receptor. Proc. Natl. Acad. Sci. U.S.A., 104, 7027-7032.
    3. Liu, W., Fei, J.Z., Kawakami, T. and Smith, S.O. (2007) Structural constraints on the transmembrane and juxtamembrane regions of the phospholamban pentamer in membrane bilayers: Gln29 and Leu52. Biophys. Biochem. Acta, 1768, 2971-2978.
    1. Takeshi Sato, Payal Pallavi, Urszula Golebiewska, Stuart McLaughlin and Steven O. Smith  Structure of the membrane reconstituted transmembrane-juxtamembrane peptide EGFR(622-660) and its interactions with Ca2+/Calmodulin. Biochemistry 2006; 45, 12704-12714.
    2. Wenyi Zhang, Takeshi Sato and Steven O. Smith NMR spectroscopy of basic/aromatic amino acid clusters in membrane proteins. Progress in Nuclear Magnetic Resonance Spectroscopy 2006; 48, 183-199.
    3. Judith Staerk, Catherine Lacout, Takeshi Sato, Steven O. Smith, William Vainchenker and Stefan N. Constantinescu An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood 2006; 107, 1864-1871.
    4. Takeshi Sato, Pascal Kienlen-Campard, Mahiuddin Ahmed, Wei Liu, Huilin Li, James I. Elliott, Saburo Aimoto, Stefan N. Constantinescu, Jean-Noel Octave and Steven O. Smith Inhibitors of amyloid toxicity based on b -sheet packing of A b 40 and A b 42. Biochemistry 2006; 45, 5503-5516.
    5. Christoph Seibert, Weiwen Ying, Svetlana Gavrilov, Fotini Tsamis, Shawn E. Kuhmann, Anandan Palani, Jayaram R. Tagat, John W. Clader, Stuart W. McCombie, Bahige M. Baroudy, Steven O. Smith, Tatjana Dragic, John P. Moore, Thomas P. Sakmar Interaction of small molecule inhibitors of HIV-1 entry with CCR5.Virology 2006; 349, 41-54.
    6. Iris A. Mastrangelo, Mahiuddin Ahmed, Takeshi Sato, Wei Liu, Chengpu Wang, Paul Hough and Steven O. Smith High-resolution Atomic Force Microscopy of Soluble A b 42 Oligomers. Journal of Molecular Biology 2006; 358, 106-119.
    7. Evan Crocker, Markus Eilers, Shivani Ahuja, Viktor Hornak, Amiram Hirshfeld, Mordechai Sheves and Steven O. Smith >Location of Trp265 in Metarhodopsin II: Implications for the Activation Mechanism of the Visual Receptor Rhodopsin. Journal of Molecular Biology 2006; 357, 163-172.
    1. Lori L. Anderson, Garland R. Marshall, Evan Crocker, Steven O. Smith and Thomas J. Baranski Motion of Carboxyl Terminus of Ga Is Restricted upon G Protein Activation. A Solution NMR Study Using Semisynthetic Ga Subunits. The Journal of Biological Chemistry 2005; 280, 31019-31025.
    2. Wei Liu, Evan Crocker, Stefan N. Constantinescu, and Steven O. Smith Helix Packing and Orientation in the Transmembrane Dimer of gp55-P of the Spleen Focus Forming Virus. Biophysical Journal 2005; 89(2), 1194-1202.
    3. Wenyi Zhang and Steven O. Smith Mechanism of Penetration of Antp(43-58) into Membrane Bilayers. Biochemistry 2005; 44, 10110-10118.
    4. Stuart McLaughlin, Steven O. Smith, Micheal J. Hayman and Diana Murray An Electrostatic Engine Model for Autoinhibition and Activation of the Epidermal Growth Factor Receptor (EGFR/ErbB) Family. Journal of General Physiology 2005; 126, 41-53.
    5. Markus Eilers, Viktor Hornak, Steven O. Smith and James B. Konopka Comparison of Class A and D G Protein-Coupled Receptors: Common Features in Structure and Activation.nbsp;Biochemistry 2005; 44, 8959-8975.
    6. Kathleen P. Howard, Wei Lui, Evan Crocker, Vikas Nanda, James Lear, William F. Degrado and Steven O. Smith Rotational Orientation of Monomers Within a Designed Homo-Oligomer Transmembrane Helical Bundle. Protein Science 2005; 14, 1019-1024.
    7. Katharina F. Kubatzky, Wei Liu, Kerri Goldgraben, Carlos Simmerling, Steven O. Smith and Stefan N. Constantinescu Structural Requirements of the Extracellular to Transmembrane Domain Junction for Erythropoietin Receptor Function. The Journal of Biological Chemistry 2005; 280, 14844-14854.
    8. Wei Liu, Evan Crocker, Wenyi Zhang, James I. Elliot, Burkhard Luy, Huilin Li, Saburo Aimoto and Steven O. Smith Structural Role of Glycine in Amyloid Fibrils Formed from Transmembrane a -Helices. Biochemistry 2005; 44, 3591-3597.
    9. Ashish B. Patel, Evan Crocker, Philip J. Reeves, Elena V. Getmanova, Markus Eilers, H. Gobind Khorana and Steven O. Smith Changes in Interhelical Hydrogen Bonding upon Rhodopsin Activation. Journal of Molecular Biology 2005; 347, 803-812.
    1. Ashish B. Patel, Evan Crocker, Markus Eilers, Amiram Hirshfeld, Mordechai Sheves and Steven O. Smith Coupling of retinal isomerization to the activation of rhodopsin. PNAS 2004; 101, 10048-10053.
    2. Alok Gambhir, Gyöngyi Hangyás-Mihályné, Irina Zaitseva, David S. Cafiso, Jiyao Wang, Diana Murray, Srinivas N. Pentyala, Steven O. Smith and Stuart McLaughlin Electrostatic Sequestration of PIP2 on Phospholipid Membranes by Basic/Aromatic Regions of Proteins. Biophysical Journal 2004; 86, 2188-2207.
    3. Crocker E, Patel AB, Eilers M, Jayaraman S, Getmanova E, Reeves PJ, Ziliox M, Khorana HG, Sheves M, and Steven O. Smith Dipolar assisted rotational resonance NMR of tryptophan and tyrosine in rhodopsin. Journal of Biomolecular NMR 2004; 29(1), 11-20.
    4. Wei Liu, Markus Eilers, Ashish B. Patel, and Steven O. Smith Helix Packing Moments Reveal Diversity and Conservation in Membrane Protein Structure. Journal of Molecular Biology 2004;337(3), 713-729.
    5. Elena Getmanova, Ashish B. Patel, Judith Klein-Seetharaman, Michele C. Loewen, Philip J. Reeves, Noga Friedman, Mordechai Sheves, Steven O. Smith, and H. Gobind Khorana NMR Spectroscopy of Phosphorylated Wild-Type Rhodopsin: Mobility of the Phosphorylated C-Terminus of Rhodopsin in the Dark and upon Light Activation. Biochemistry 2004; 43(4), 1126-1133.
    1. Nadine Seubert, Yohan Royer, Judith Staerk, Katharina F. Kubatzky, Virginie Moucadel, Shyam Krishnakumar, Steven O. Smith, and Stefan N. Constantinescu Active and Inactive Orientations of the Transmembrane and Cytosolic Domains of the Erythropoietin Receptor Dimer. Molecular Cell 2003; 12, 1239-1250
    2. Zhang W, Crocker E, McLaughlin S, and Steven O. Smith Binding of Peptides with Basic and Aromatic Residues to Bilayer Membranes: phenylalanine in the myristoylated alanine-rich C kinase substrate effector domain penetrates into the hydrophobic core of the bilayer. J. Biol. Chem. 2003; 278(24), 21459-21466
    3. Wei Liu, Evan Crocker, David J. Siminovitch, and Steven O. Smith Role of Side-Chain Conformational Entropy in Transmembrane Helix Dimerization of Glycophorin A. Biophysical Journal 2003;84(2), 1263-1271
    4. Jennifer C. Lin, William Parrish, Markus Eilers, Steven O. Smith, and James B. Konopka Aromatic Residues at the Extracellular Ends of Transmembrane Domains 5 and 6 Promote Ligand Activation of the G Protein-Coupled a -Factor Receptor. Biochemistry 2003;42(2), 293-301
    1. Eilers, M., Ying, W., Reeves, P.J., Khorana, H.G. and Smith, S.O. Magic angle spinning nuclear magnetic resonance of isotopically labeled rhodopsin. Methods Enzymol. 2002;343, 212-222
    2. Pablo M. Irusta, Yue Luo, Omar Bakht, Char-Chang Lai, Steven O. Smith, and Daniel DiMaio Definition of an Inhibitory Juxtamembrane WW-like Domain in the Platelet-derived Growth Factor b Receptor. J Biol Chem 2002;277(41), 38627-38634
    3. Brigitte Schobert, Jill Cupp-Vickery, Viktor Hornak, Steven O. Smith, Janos K. Lanyi Crystallographic Structure of the K Intermediate of Bacteriorhodopsin: Conservation of Free Energy after Photoisomerization of the Retinal. Journal of Molecular Biology 2002;321(4), 715-726
    4. Steven O. Smith, Charles Smith, Srinivasan Shekar, Olve Peersen, Martine Ziliox, and, and Saburo Aimoto Transmembrane Interactions in the Activation of the Neu Receptor Tyrosine Kinase. Biochemistry 2002;41(30), 9321-9332
    5. Markus Eilers, Ashish B. Patel, Wei Liu, and Steven O. Smith Comparison of Helix Interactions in Membrane and Soluble a -Bundle Proteins. Biophysical Journal2002;82(5), 2720-2736
    6. Steven O. Smith, Markus Eilers, David Song, Evan Crocker, Weiwen Ying, Michel Groesbeek, Guenter Metz, Martine Ziliox, and Saburo Aimoto Implications of Threonine Hydrogen Bonding in the Glycophorin A Transmembrane Helix Dimer. Biophysical Journal 2002;82(5), 2476-2486
    1. Steven O. Smith, Toru Kawakami, Wei Liu, Martine Ziliox, and Saburo Aimoto Helical Structure of Phospholamban in Membrane Bilayers. Journal of Molecular Biology 2001;313(5), 1139-1148
    2. Steven O. Smith, David Song, Srinivasan Shekar, Michel Groesbeek, Martine Ziliox, and Saburo Aimoto Structure of the Transmembrane Dimer Interface of Glycophorin A in Membrane Bilayers . Biochemistry 2001;40(22), 6553-6558
    1. Weiwen Ying, Scott E. Irvine, Richard A. Beekman, David J. Siminovitch, and Steven O. Smith Deuterium NMR Reveals Helix Packing Interactions in Phospholamban. Journal of the American Chemical Society 2000; 122(45); 11125-1112
    2. Dragic,T., Trkola, A., Thompson, D.A.D., Cormier, E.G., Kajumo, F.A., Maxwell, E., Lin, S.W., Ying, W., Smith, S.O., Sakmar, T.P. and Moore, J.P. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc. Natl. Acad. Sci. USA 97, 5639-5644 (2000)
    3. Eilers, M., Shekar, S.C., Shieh, T., Smith, S.O. and Fleming, P.J. Internal packing of helical membrane proteins. Proc. Natl. Acad. Sci. USA 97, 5796-5801 (2000)
    4. Zahn, T.J., Eilers, M., Guo, Z.M., Ksebati, M.B., Simon, M., Scholten, J.D., Smith, S.O. and Gibbs, R.A. Evaluation of isoprenoid conformation in solution and in the active site of protein-farnesyl transferase using carbon-13 labeling in conjunction with solution- and solid-state NMR. J. Am. Chem. Soc. 122, 7153-7164 (2000)
    1. Constantinescu, S.N., Liu, X.D., Beyer, W., Fallon, A., Shekar, S., Henis, Y.I., Smith, S.O. and Lodish, H.F. Activation of the erythropoietin receptor by the gp55-P viral envelope protein is determined by a single amino acid EMBO J. 18, 3334-3347 (1999)
    2. Eilers, M., Reeves, P.J., Ying, W., Khorana, H.G. and Smith, S.O. Magic angle spinning NMR of the protonated retinylidene Schiff base in rhodopsin: Expression of 15N-lysine- and 13C-glycine-labeled opsin in a stable cell line. Proc. Natl. Acad. Sci. USA 96, 487-492 (1999)
    3. Klein, O., Kegler-Ebo, D., Su, J., Smith, S.O. and Dimaio, D. The bovine papillomavirus E5 protein requires a juxtamembrane negative charge for activation of the platelet-derived growth factor beta receptor and transformation of C127 cells. J. Virology 73, 3264-3272 (1999)
    4. Javadpour, M.M.,Eilers, M., Groesbeek, M. and Smith, S.O. 
 Helix Packing in Polytopic Membrane Proteins: Role of Glycine in Transmembrane Helix Association.Biophys. J. 77, 1609-1618 (1999)
    5. Reeves, P.J., Klein-Seetharaman, J., Getmanova, E.V., Eilers, M., Loewen, M.C., Smith, S.O. and Khorana, H.G. 
Expression and purification of rhodopsin and its mutants from stable mammalian cell lines: application to NMR studies. 
Biochem. Soc. Trans. 27, 950-955 (1999).
    1. Han, M.,Groesbeek, M., Smith, S.O. and Sakmar, T.P. The role of the C9 methyl group in rhodopsin activation: characterization of mutant opsin with the artificial chromophore 11-cis-9-demethylretinal. Biochemistry 37, 538-545 (1998)
    2. Han, M., Smith, S.O. and Sakmar, T.P. Constitutive activation of opsin by mutation of methionine 257 on transmembrane helix 6. Biochemistry 37, 8253-8261 (1998)
    3. Klein, O., Polack, G.W., Surti, T., Kegler-Ebo, D., Smith, S.O. and Dimaio, D. Role of glutamine 17 of the bovine papillomavirus E5 protein in platelet-derived growth factor beta receptor activation and cell transformation. J. Virology 72, 8921-8932 (1998)
    4. Surti, T., Klein, O., Aschheim, K., Dimaio, D. and Smith, S.O. Structural models of the bovine papillomavirus E5 protein. Proteins: Struct. Funct. Genet. 33, 601-612 (1998)
    1. Arkin, I.T., Adams, P.D., Brunger, A.T., Aimoto, S., Engelman, D.M. and Smith, S.O. Structure of the transmembrane cysteine residues in phospholamban. J. Membr. Biol. 155, 199-206 (1997)
    2. Arkin, I.T., Adams, P.D., Brunger, A.T., Smith, S.O. and Engelman, D.M. Structural perspectives of phospholamban, a helical transmembrane pentamer. Annu. Rev. Biophys. Biomol. Struct. 26, 157-179 (1997)
    3. Groesbeek, M. and Smith, S.O. Synthesis of19-fluororetinal and 20-fluororetinal. J. Org. Chem. 62, 3638-3641 (1997)
    4. Han, M., Groesbeek, M., Sakmar, T.P. and Smith, S.O. The C9 methyl group of retinal interacts with glycine-121 in rhodopsin. Proc. Natl. Acad. Sci. USA 94, 13442-13447 (1997)
    5. Han, M., Lou, J.H., Nakanishi, K., Sakmar, T.P. and Smith, S.O. Partial agonist activity of 11-cis-retinal in rhodopsin mutants. J. Biol. Chem. 272, 23081-23085 (1997).
    6. Petti, L.M., Reddy, V., Smith, S.O. and Dimaio, D. Identification of amino acids in the transmembrane and juxtamembrane domains of the platelet-derived growth factor receptor required for productive interaction with the bovine papillomavirus E5 protein. J. Virology 71, 7318-7327 (1997)
    7. Sansom, M.S., Smith, G.R., Smart, O.S. and Smith, S.O. Channels formed by the transmembrane helix of phospholamban: a simulation study. Biophys. Chem. 69, 269-281 (1997)
    8. Shieh, T., Han, M., Sakmar, T.P. and Smith, S.O. The steric trigger in rhodopsin activation. J. Mol. Biol. 269, 373-384 (1997)
    1. Arkin, I.T., Mackenzie, K., Fisher, L., Aimoto, S., Engelman, D. and Smith, S.O. Mapping the lipid exposed surface of membrane proteins. Nature Struct. Biol. 3, 240-243 (1996)
    2. Han, M., Lin, S., Smith, S.O. and Sakmar, T.P. The effects of amino acid replacements of glycine 121 on transmembrane helix 3 of rhodopsin. J. Biol. Chem. 271, 32330-32336 (1996)
    3. Han, M., Lin, S., Minkova, M., Smith, S.O. and Sakmar, T.P. Functional helix-helix interactions in rhodopsin: replacement of phenylalanine 261 by alanine causes reversion of phenotype of a glycine 121 replacement mutant. J. Biol. Chem. 271, 32337-32342 (1996)
    4. Ludlam, C. Arkin, I.T., Liu, X.-M., Rothman, M.S., Rath, P., Aimoto, S., Smith, S.O., Engelman, D. and Rothschild, K.J. FTIR spectroscopy and site-directed isotope labeling as a probe of local secondary structure in the transmembrane domain of phospholamban Biophys. J. 70, 1728-1736 (1996)
    5. Metz, G., Ziliox, M. and Smith, S.O. Towards quantitative CP-MAS NMR Solid-State NMR. 7, 155-160 (1996)
    6. Smith, S.O. NMR studies on the structure and function of rhodopsin. Behav. Brain Sci. 18, 488-489 (1996)
    7. Sanders, C.R., Czerski, L., Vinogradova, O., Badola, P., Song, D. and Smith, S.O. E.coli diacylglycerol kinase is an a -helical polytopic membrane protein and can spontaneously insert into pre-formed lipid vesicles. Biochemistry 35, 8610-8618 (1996)
    8. Smith, S.O., Smith, C.S. and Bormann, B.J. Strong hydrogen bonding interactions involving a buried glutamic acid in the transmembrane domain of the neu/erbB-2 receptor. Nature Struct. Biol. 3, 252-258 (1996).
    9. Smith, S.O., Aschheim, K. and Groesbeek, M. Magic angle spinning NMR of membrane proteins. Quart. Rev. Biophys. 29, 395-449 (1996)
    1. Han, M. and Smith, S.O. High resolution structural studies of the retinal-glu113 interaction in rhodopsin. Biophys. Chem. 56, 23-30 (1995)
    2. Han, M. and Smith, S.O. NMR constraints on the location of the retinal chromophore in rhodopsin and bathorhodopsin. Biochemistry 34, 1425-1432 (1995)Corrections.
    3. Arkin IT, Rothman M, Ludlam CF, Aimoto S, Engelman DM, Rothschild KJ, and Smith, S.O. Structural model of the phospholamban ion channel complex in phospholipid membranes. J. Mol. Biol. 248(4) 824-34 (1995)
    4. Metz, G., Howard, K.P., van Liemt, W.B.S., Prestegard, J.H., Lugtenburg, J. and Smith, S.O. NMR studies of ubiquinone location in oriented model membranes: evidence for a single motionally averaged population. J. Am. Chem. Soc. 117, 564-565 (1995)
    5. Peersen, O.B., Groesbeek, M., Aimoto, S. and Smith, S.O. Analysis of rotational resonance NMR magnetization exchange curves of crystalline peptides. J. Am. Chem. Soc. 27, 7228-7237 (1995)
    6. Smith, S.O. and Bormann, B.J. Determination of helix-helix interactions in membranes by rotational resonance NMR. Proc. Natl. Acad. Sci. USA 92, 488-491 (1995)