Research Topics
| STEVEN SINESummaryAffiliation: Mayo Clinic Country: USA Publications
Research Grants
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Detail Information
Publications
End-plate acetylcholine receptor: structure, mechanism, pharmacology, and diseaseSteven M Sine
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Physiol Rev 92:1189-234. 2012..Recent studies provide an increasingly detailed picture of the structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction...- Naturally occurring mutations at the acetylcholine receptor binding site independently alter ACh binding and channel gatingSteven M Sine
Receptor Biology Laboratory, Department of Physiology and Biophysics, and Mayo Foundation, Rochester, MN 55905, USA
J Gen Physiol 120:483-96. 2002..The overall results show that key residues at the ACh binding site differentially stabilize the agonist bound to closed, open and desensitized states, and provide a set point for gating of the channel... 
Toward atomic-scale understanding of ligand recognition in the muscle nicotinic receptorSteven M Sine
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Curr Med Chem 11:559-67. 2004..The results have important implications for design of drugs targeting nicotinic receptors and members of the superfamily of pentameric ligand-gated ion channels...- Mechanistic diversity underlying fast channel congenital myasthenic syndromesSteven M Sine
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Medical School, Rochester, Minnesota 55905, USA
Ann N Y Acad Sci 998:128-37. 2003..This review focuses on new mechanisms underlying the FCCMS... - Recent structural and mechanistic insights into endplate acetylcholine receptorsSteven M Sine
Receptor Biology Laboratory, Departments of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Ann N Y Acad Sci 1132:53-60. 2008..Structural models of the human AChR enable precise mapping of disease-causing mutations, while studies of the speed with which single AChR channels open and close cast light on pathogenic mechanisms... - Recent advances in Cys-loop receptor structure and functionSteven M Sine
Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Nature 440:448-55. 2006..Namely, analyses of disease-causing mutations have clarified receptor structure-function relationships as well as mechanisms governing the postsynaptic response... - The nicotinic receptor ligand binding domainSteven M Sine
Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905, USA
J Neurobiol 53:431-46. 2002.... - On the origin of ion selectivity in the Cys-loop receptor familySteven M Sine
Receptor Biology Laboratory, Departments of Physiology and Biomedical Engineering and Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
J Mol Neurosci 40:70-6. 2010.... - Lysine scanning mutagenesis delineates structural model of the nicotinic receptor ligand binding domainSteven M Sine
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Foundation, Rochester, Minnesota 55905, USA
J Biol Chem 277:29210-23. 2002..The overall results suggest that lysine scanning can provide the basis for structural modeling of other members of the AChR superfamily as well as of other proteins with repeating structures delimiting a hydrophobic core... - Invariant aspartic Acid in muscle nicotinic receptor contributes selectively to the kinetics of agonist bindingWon Yong Lee
Department of Physiology and Biophysics, Mayo Clinic College of Medicine, 200 First St, SW, MSB 1-35, Rochester, MN 55905, USA
J Gen Physiol 124:555-67. 2004..The specific effect of alphaD89N on ACh association suggests that interdomain hydrogen bonding positions alphaW149 for optimal interaction with ACh... - Curariform antagonists bind in different orientations to acetylcholine-binding proteinFan Gao
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Clinic Department of Pharmacology, Mayo Graduate School, Rochester, Minnesota 55905, USA
J Biol Chem 278:23020-6. 2003..Thus structurally similar ligands can adopt distinct orientations at receptor binding sites, posing challenges for interpreting structure-activity relationships for many drugs... - Initial coupling of binding to gating mediated by conserved residues in the muscle nicotinic receptorNuriya Mukhtasimova
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
J Gen Physiol 126:23-39. 2005..Thus, interplay between these three conserved residues relays the initial conformational change from the ACh binding site toward the ion channel... - An intersubunit trigger of channel gating in the muscle nicotinic receptorNuriya Mukhtasimova
Department of Physiology and Biomedical Engineering, Receptor Biology Laboratory, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
J Neurosci 27:4110-9. 2007..Thus, the Tyr-Asn pair is an intersubunit trigger of rapid and efficient gating of muscle nicotinic receptors... - Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdownXin-ming Shen
Neuromuscular Research Laboratory and Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
Ann Neurol 60:128-36. 2006..Efficient and selective knockdown of the mutant allele holds promise of therapeutic gene silencing... - Agonist-mediated conformational changes in acetylcholine-binding protein revealed by simulation and intrinsic tryptophan fluorescenceFan Gao
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
J Biol Chem 280:8443-51. 2005..The collective findings showed that ACh initially establishes close register of conserved Trps from adjacent subunits and then draws the C-loop inward to occlude the entrance to the binding cavity... - Mutation causing severe myasthenia reveals functional asymmetry of AChR signature cystine loops in agonist binding and gatingXin Ming Shen
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA
J Clin Invest 111:497-505. 2003..The overall findings reveal functional asymmetry between cys-loops of the different AChR subunits in contributing to ACh binding and channel gating... - Detection and trapping of intermediate states priming nicotinic receptor channel openingNuriya Mukhtasimova
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Nature 459:451-4. 2009..Thus, a change in binding-site conformation primes the AChR for channel opening in a process that enables selective activation by ACh while maximizing the speed and efficiency of the biological response... - Subunit-specific contribution to agonist binding and channel gating revealed by inherited mutation in muscle acetylcholine receptor M3-M4 linkerXin-ming Shen
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA
Brain 128:345-55. 2005..The overall studies reveal subunit asymmetry in the contributions of the M3-M4 loops in optimizing AChR activation through allosteric links to the channel and the agonist binding site... - Principal pathway coupling agonist binding to channel gating in nicotinic receptorsWon Yong Lee
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Nature 438:243-7. 2005..The series of interresidue couplings identified here constitutes a primary allosteric pathway that links neurotransmitter binding to channel gating... - Congenital myasthenia-related AChR delta subunit mutation interferes with intersubunit communication essential for channel gatingXin Ming Shen
Muscle Research Laboratory, Department of Neurology, Receptor Biology Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA
J Clin Invest 118:1867-76. 2008..Thus, deltaL42 is part of an intersubunit network that enables ACh binding to rapidly open the AChR channel, which may be compromised in patients with CM... - Control of cation permeation through the nicotinic receptor channelHai Long Wang
Receptor Biology Laboratory, Department of Physiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
PLoS Comput Biol 4:e41. 2008.... - Further observations in congenital myasthenic syndromesAndrew G Engel
Department of Neurology and Muscle Research Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Ann N Y Acad Sci 1132:104-13. 2008..4, MuSK, and Dok-7. Moreover, emerging genotype-phenotype correlations are providing clues for targeted mutation analysis. This review focuses on the recent observations in selected CMS... - Nicotinic receptor interloop proline anchors beta1-beta2 and Cys loops in coupling agonist binding to channel gatingWon Yong Lee
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
J Gen Physiol 132:265-78. 2008..The overall results indicate that alphaPro 272 functionally couples to flanking Val residues extending from the beta1-beta2 and Cys loops within the ACh binding to channel opening transduction pathway... - Single-channel current through nicotinic receptor produced by closure of binding site C-loopHai Long Wang
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
Biophys J 96:3582-90. 2009..This approach of applying Biology Boltzmann transport Monte Carlo simulation can be used to further investigate the binding to gating transduction mechanism and the structural bases for ion selection and translocation... - What have we learned from the congenital myasthenic syndromesAndrew G Engel
Department of Neurology and Muscle Research Laboratory, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
J Mol Neurosci 40:143-53. 2010..Mutations in EP-specific proteins also prompted expression studies that proved pathogenicity, highlighted important functional domains of the abnormal proteins, and pointed to rational therapy... - Current understanding of congenital myasthenic syndromesAndrew G Engel
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA
Curr Opin Pharmacol 5:308-21. 2005..Recent crystallography studies of choline acetyltransferase and homology structural models of the acetylcholine receptor are providing further clues to how point mutations alter protein function... - Binding to gating transduction in nicotinic receptors: Cys-loop energetically couples to pre-M1 and M2-M3 regionsWon Yong Lee
Receptor Biology Laboratory and Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
J Neurosci 29:3189-99. 2009..Thus, the extracellular beta1-beta2 and Cys-loops bridge the pre-M1 domain and M2-M3 linker to transduce agonist binding into channel gating... - Sleuthing molecular targets for neurological diseases at the neuromuscular junctionAndrew G Engel
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA
Nat Rev Neurosci 4:339-52. 2003 - The spectrum of congenital myasthenic syndromesAndrew G Engel
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA
Mol Neurobiol 26:347-67. 2002..Future studies will likely uncover new types of CMS that reside in molecules governing quantal release, organization of the synaptic basal lamina, and expression and aggregation of AChR on the postsynaptic junctional folds... - Congenital myasthenic syndromes: progress over the past decadeAndrew G Engel
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA
Muscle Nerve 27:4-25. 2003..In a subset of CMS patients, endplate AChR deficiency is caused by mutations in rapsyn, a molecule that plays a critical role in concentrating AChR in the postsynaptic membrane... - Congenital myasthenic syndromes: A diverse array of molecular targetsAndrew G Engel
Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905
J Neurocytol 32:1017-37. 2003.... - Congenital myasthenic syndromes: multiple molecular targets at the neuromuscular junctionAndrew G Engel
Neuromuscular Disease Research Laboratory, Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
Ann N Y Acad Sci 998:138-60. 2003..In a subset of CMS patients, endplate AChR deficiency is caused by mutations in rapsyn, a molecule that plays a critical role in concentrating AChR in the postsynaptic membrane... - Solution NMR of acetylcholine binding protein reveals agonist-mediated conformational change of the C-loopFan Gao
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester MN 55905, USA
Mol Pharmacol 70:1230-5. 2006..The collective findings suggest a structural mechanism for agonist recognition in AChBP and related Cys-loop receptors... - Curariform antagonists bind in different orientations to the nicotinic receptor ligand binding domainHai-long Wang
Receptor Biology Laboratory, Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota 55905, USA
J Biol Chem 278:32284-91. 2003..The overall mutagenesis and computational results show that despite their similar structures, d-TC and metocurine bind in distinctly different orientations to the adult human AChR... - New horizons for congenital myasthenic syndromesAndrew G Engel
Neuromuscular Research Laboratory, Department of Neurology, Mayo Clinic, Rochester, Minnesota Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, and Department of Neurology, Mayo Clinic, Rochester, Minnesota
Ann N Y Acad Sci 1275:54-62. 2012.... - Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1Ines Ibanez-Tallon
Laboratory of Molecular Biology, Howard Hughes Medical Institute, New York, NY 10021, USA
Neuron 33:893-903. 2002.... - Subunit-selective contribution to channel gating of the M4 domain of the nicotinic receptorCecilia Bouzat
Instituto de Investigaciones Bioquimicas, UNS CONICET, Bahia Blanca, Argentina
Biophys J 82:1920-9. 2002..Thus, we identify subunit-specific contributions to channel gating of equivalent residues in M4 and elucidate the underlying mechanistic and structural bases... - Residues in the epsilon subunit of the nicotinic acetylcholine receptor interact to confer selectivity of waglerin-1 for the alpha-epsilon subunit interface siteBrian E Molles
Department of Pharmacology, Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA92093-0636, USA
Biochemistry 41:7895-906. 2002..We use the binding and interaction energies for Wtx-1 to generate structural models of the alpha-epsilon, alpha-gamma, and alpha-delta binding sites containing the nonhomologous insertion... - Mechanism of tacrine block at adult human muscle nicotinic acetylcholine receptorsRichard J Prince
School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
J Gen Physiol 120:369-93. 2002..Overall, the best description of our data was obtained with a model that combined two binding sites in the open channel with a single site in the closed state of the receptor... - Alpha-conotoxins ImI and ImII target distinct regions of the human alpha7 nicotinic acetylcholine receptor and distinguish human nicotinic receptor subtypesMichael Ellison
Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112, USA
Biochemistry 43:16019-26. 2004..Collectively, the data show that while alpha-ImI targets the classical competitive ligand binding site in a subtype selective manner, alpha-ImII is a probe of a novel inhibitory site in homomeric alpha7 nAChRs... - Ligand-induced conformational change in the alpha7 nicotinic receptor ligand binding domainRichard H Henchman
Howard Hughes Medical Institute, NSF Center for Theoretical Biophysics, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
Biophys J 88:2564-76. 2005.... 
The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitizationCecilia Bouzat
Instituto de Investigaciones Bioquimicas, Universidad Nacional del Sur Consejo Nacional de Investigaciones CientÃficas y Técnicas, Bahia Blanca 8000, Argentina
J Neurosci 28:7808-19. 2008....- Single-channel kinetic analysis of chimeric alpha7-5HT3A receptorsDiego Rayes
Instituto de Investigaciones Bioquimicas, Camino La Carrindanga Km 7, 8000 Bahia Blanca, Argentina
Mol Pharmacol 68:1475-83. 2005..Channel closing and desensitization occur at similar rates and account for the invariant open and closed time distributions... - Structural basis for epibatidine selectivity at desensitized nicotinic receptorsRichard A Pennington
School of Biological Sciences, University of Manchester, G38 Stopford Bldg, Oxford Rd, Manchester M13 9PT, United Kingdom
Mol Pharmacol 67:123-31. 2005..The structural basis for epibatidine selectivity is explained by computational docking of epibatidine to a homology model of the alpha-gamma binding site... - Identification of residues at the alpha and epsilon subunit interfaces mediating species selectivity of Waglerin-1 for nicotinic acetylcholine receptorsBrian E Molles
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093 0636, USA
J Biol Chem 277:5433-40. 2002..The overall results show that non-conserved residues at the nAChR binding site, although not crucial for activation by ACh, govern the potency of neuromuscular toxins... - Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channelCecilia Bouzat
Instituto de Investigaciones Bioquimicas, UNS-CONICET, Bahia Blanca 8000, Argentina
Nature 430:896-900. 2004..Structural modelling reveals a network of interacting loops between binding and pore domains that mediates this allosteric coupling process... - Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulationRichard H Henchman
Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, USA
Biophys J 85:3007-18. 2003..Furthermore, the shape of the asymmetry with binding sites of differing affinity for acetylcholine, characteristic of other nicotinic receptors, may be a natural property of the relaxed, activatable state of alpha7... - Nanosecond-timescale conformational dynamics of the human alpha7 nicotinic acetylcholine receptorXiaolin Cheng
Howard Hughes Medical Institute, National Science Foundation Center for Theoretical Biophysics, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA
Biophys J 93:2622-34. 2007..The resulting concerted motion causes a downward shift of the M2 helices that disrupts a hydrophobic girdle formed by 9' and 13' residues... - Barriers to ion translocation in cationic and anionic receptors from the Cys-loop familyIvaylo Ivanov
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093 0365, USA
J Am Chem Soc 129:8217-24. 2007..Thus, the overall electrostatics and the presence of rings of charged residues at the entrance and exit of the channels were sufficient to explain the experimentally observed anion and cation selectivity... - Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptorsXiaolin Cheng
Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America
PLoS Comput Biol 2:e134. 2006.... - Morantel allosterically enhances channel gating of neuronal nicotinic acetylcholine alpha 3 beta 2 receptorsTse Yu Wu
Department of Chemistry, Grinnell College, Grinnell, Iowa 50112, USA
Mol Pharmacol 74:466-75. 2008....
Research Grants
- Allosteric Coupling in Homomeric Cys-loop ReceptorsSTEVEN SINE; Fiscal Year: 2009..Knowledge of how Cys-loop receptors operate at the molecular level is essential to developing therapeutic strategies and drugs with fewer side effects. ..
- Allosteric Coupling in Homomeric Cys-loop ReceptorsSTEVEN SINE; Fiscal Year: 2007..Knowledge of how Cys-loop receptors operate at the molecular level is essential to developing therapeutic strategies and drugs with fewer side effects. ..
- STRUCTURE AND FUNCTION OF THE ACETYLCHOLINE RECEPTORSTEVEN SINE; Fiscal Year: 2000....
- STRUCTURE AND BIOPHYSICS OF THE ACETYLCHOLINE RECEPTORSTEVEN SINE; Fiscal Year: 1993..The insights gained may provide similar insights for the entire superfamily of neurotransmitter-gated ion channels...
- Structure and Function of Acetylcholine ReceptorsSteven M Sine; Fiscal Year: 2010..Understanding both structures and molecular mechanisms of post-synaptic receptors would enable design of more specific drugs. ..