Cryo-EM structure of 5-HT3A receptor in its resting conformation

Nature Communications

Volumn 9, Issue 1, 2018, Pages

  Basak, Sandip ^a   Gicheru, Yvonne ^a   Samanta, Amrita ^a   Molugu, Sudheer Kumar ^a   Huang, Wei ^a   Fuente, Maria La De ^a   Hughes, Taylor ^a   Taylor, Derek J ^a   Nieman, Marvin T ^a   Moiseenkova Bell, Vera ^a   Chakrapani, Sudha ^a  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SEROTONIN 3A RECEPTOR; ION; LIGAND; RECOMBINANT PROTEIN; SEROTONIN; SEROTONIN 3 RECEPTOR;

CANCER; CHEMICAL BINDING; CRYSTAL STRUCTURE; DRUG; LIGAND; MICROSCOPY; MOVEMENT; PATHOLOGY; PROTEIN;

ARTICLE; BINDING SITE; CODON; CONFORMATION; CONTROLLED STUDY; CRYSTAL STRUCTURE; ELECTRON MICROSCOPY; HUMAN; HYDROPHOBICITY; ION TRANSPORT; LIGAND BINDING; MOUSE; NONHUMAN; SURFACE AREA; THREE DIMENSIONAL IMAGING; ANIMAL; CHEMISTRY; CRYOELECTRON MICROSCOPY; ELECTROPHYSIOLOGY; FEMALE; MOLECULAR CLONING; OOCYTE; PROTEIN CONFORMATION; PROTEIN DOMAIN; ULTRASTRUCTURE; XENOPUS LAEVIS;

ANIMALS; CLONING, MOLECULAR; CRYOELECTRON MICROSCOPY; ELECTROPHYSIOLOGY; FEMALE; IONS; LIGANDS; MICE; OOCYTES; PROTEIN CONFORMATION; PROTEIN DOMAINS; RECEPTORS, SEROTONIN, 5-HT3; RECOMBINANT PROTEINS; SEROTONIN; XENOPUS LAEVIS;

EID: 85041650874     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/s41467-018-02997-4     Document Type: Article

References (60)

1. Maricq, A. V., Peterson, A. S., Brake, A. J., Myers, R. M. &Julius, D. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254, 432-437 (1991).
2. Lummis, S. C. 5-HT(3) receptors. J. Biol. Chem. 287, 40239-40245 (2012).
3. Niesler, B., Frank, B., Kapeller, J. &Rappold, G. A. Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. Gene 310, 101-111 (2003).
4. Engel, M., Smidt, M. P. &van Hooft, J. A. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front. Cell Neurosci. 7, 76 (2013).
5. Gehlert, D. R., Gackenheimer, S. L., Wong, D. T. &Robertson, D. W. Localization of 5-HT3 receptors in the rat brain using [3H]LY278584. Brain Res. 553, 149-154 (1991).
6. Gershon, M. D. Review article: serotonin receptors and transporters-roles in normal and abnormal gastrointestinal motility. Aliment. Pharmacol. Ther. 20 (Suppl 7), 3-14 (2004).
7. Costall, B. &Naylor, R. J. 5-HT3 receptors. Curr. Drug Targets CNS Neurol. Disord. 3, 27-37 (2004).
8. Perwitasari, D. A. et al. Anti-emetic drugs in oncology: pharmacology and individualization by pharmacogenetics. Int. J. Clin. Pharm. 33, 33-43 (2011).
9. Kato, S. Role of serotonin 5-HT(3) receptors in intestinal inflammation. Biol. Pharm. Bull. 36, 1406-1409 (2013).
10. Spiller, R. C. Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome. Curr. Opin. Pharmacol. 11, 68-74 (2011).
11. Hilf, R. J. &Dutzler, R. X-ray structure of a prokaryotic pentameric ligandgated ion channel. Nature 452, 375-379 (2008).
12. Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J. Mol. Biol. 346, 967-989 (2005).
13. Morales-Perez, C. L., Noviello, C. M. &Hibbs, R. E. X-ray structure of the human alpha4beta2 nicotinic receptor. Nature 538, 411-415 (2016).
14. Hibbs, R. E. &Gouaux, E. Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474, 54-60 (2011).
15. Du, J., Lu, W., Wu, S., Cheng, Y. &Gouaux, E. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature 526, 224-229 (2015).
16. Hassaine, G. et al. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature 512, 276-281 (2014).
17. Miller, P. S. &Aricescu, A. R. Crystal structure of a human GABAA receptor. Nature 512, 270-275 (2014).
18. Basak, S., Schmandt, N., Gicheru, Y. &Chakrapani, S. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. Elife 6, e23886 (2017).
19. Sauguet, L. et al. Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation. Proc. Natl Acad. Sci. USA 111, 966-971 (2014).
20. Connolly, C. N. Trafficking of 5-HT(3) and GABA(A) receptors (review). Mol. Membr. Biol. 25, 293-301 (2008).
21. Peters, J. A. et al. The 5-hydroxytryptamine type 3 (5-HT3) receptor reveals a novel determinant of single-channel conductance. Biochem. Soc. Trans. 32, 547-552 (2004).
22. Baptista-Hon, D. T., Deeb, T. Z., Lambert, J. J., Peters, J. A. &Hales, T. G. The minimum M3-M4 loop length of neurotransmitter-activated pentameric receptors is critical for the structural integrity of cytoplasmic portals. J. Biol. Chem. 288, 21558-21568 (2013).
23. Pless, S. A. &Lynch, J. W. Ligand-specific conformational changes in the alpha1 glycine receptor ligand-binding domain. J. Biol. Chem. 284, 15847-15856 (2009).
24. Hansen, S. B. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J. 24, 3635-3646 (2005).
25. Chang, Y. &Weiss, D. S. Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism. Nat. Neurosci. 5, 1163-1168 (2002).
26. Brams, M. et al. A structural and mutagenic blueprint for molecular recognition of strychnine and d-tubocurarine by different cys-loop receptors. PLoS Biol. 9, e1001034 (2011).
27. Yu, R. et al. Agonist and antagonist binding in human glycine receptors. Biochemistry 53, 6041-6051 (2014).
28. Davies, P. A. et al. The 5-HT3B subunit is a major determinant of serotoninreceptor function. Nature 397, 359-363 (1999).
29. Monk, S. A., Williams, J. M., Hope, A. G. &Barnes, N. M. Identification and importance of N-glycosylation of the human 5-hydroxytryptamine3A receptor subunit. Biochem. Pharmacol. 68, 1787-1796 (2004).
30. Althoff, T., Hibbs, R. E., Banerjee, S. &Gouaux, E. X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. Nature 512, 333-337 (2014).
31. Livesey, M. R., Cooper, M. A., Lambert, J. J. &Peters, J. A. Rings of charge within the extracellular vestibule influence ion permeation of the 5-HT3A receptor. J. Biol. Chem. 286, 16008-16017 (2011).
32. Sine, S. M., Wang, H. L., Hansen, S. &Taylor, P. On the origin of ion selectivity in the Cys-loop receptor family. J. Mol. Neurosci. 40, 70-76 (2010).
33. Lee, J. &Kim, S. H. Water polygons in high-resolution protein crystal structures. Protein Sci. 18, 1370-1376 (2009).
34. Sauguet, L. et al. Structural basis for ion permeation mechanism in pentameric ligand-gated ion channels. EMBO J. 32, 728-741 (2013).
35. Marcus, Y. Ionic radii in aqueous solution. Chem. Rev. 88, 1475-1498 (1988).
36. Thompson, A. J. &Lummis, S. C. A single ring of charged amino acids at one end of the pore can control ion selectivity in the 5-HT3 receptor. Br. J. Pharmacol. 140, 359-365 (2003).
37. Panicker, S., Cruz, H., Arrabit, C. &Slesinger, P. A. Evidence for a centrally located gate in the pore of a serotonin-gated ion channel. J. Neurosci. 22, 1629-1639 (2002).
38. Lee, W. Y., Free, C. R. &Sine, S. M. Nicotinic receptor interloop proline anchors beta1-beta2 and Cys loops in coupling agonist binding to channel gating. J. Gen. Physiol. 132, 265-278 (2008).
39. Grosman, C., Salamone, F. N., Sine, S. M. &Auerbach, A. The extracellular linker of muscle acetylcholine receptor channels is a gating control element. J. Gen. Physiol. 116, 327-340 (2000).
40. daCosta, C. J., Dey, L., Therien, J. P. &Baenziger, J. E. A distinct mechanism for activating uncoupled nicotinic acetylcholine receptors. Nat. Chem. Biol. 9, 701-707 (2013).
41. Price, K. L., Lillestol, R. K., Ulens, C. &Lummis, S. C. Varenicline interactions at the 5-HT3 receptor ligand binding site are revealed by 5-HTBP. ACS Chem. Neurosci. 6, 1151-1157 (2015).
42. Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligandbinding domain of nicotinic receptors. Nature 411, 269-276 (2001).
43. Zhong, W. et al. From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor. Proc. Natl Acad. Sci. USA 95, 12088-12093 (1998).
44. Noam, Y., Wadman, W. J. &van Hooft, J. A. On the voltage-dependent Ca2 +block of serotonin 5-HT3 receptors: a critical role of intracellular phosphates. J. Physiol. 586, 3629-3638 (2008).
45. Carland, J. E. et al. Mutagenic analysis of the intracellular portals of the human 5-HT3A receptor. J. Biol. Chem. 288, 31592-31601 (2013).
46. Miller, P. S. et al. Structural basis for GABAA receptor potentiation by neurosteroids. Nat. Struct. Mol. Biol. 24, 986-992 (2017).
47. MacKenzie, D., Arendt, A., Hargrave, P., McDowell, J. H. &Molday, R. S. Localization of binding sites for carboxyl terminal specific anti-rhodopsin monoclonal antibodies using synthetic peptides. Biochemistry 23, 6544-6549 (1984).
48. Zhang, Z. &Chen, J. Atomic structure of the cystic fibrosis transmembrane conductance regulator. Cell 167, 1586-1597 e1589 (2016).
49. Potter, C. S. et al. Leginon: a system for fully automated acquisition of 1000 electron micrographs a day. Ultramicroscopy 77, 153-161 (1999).
50. Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331-332 (2017).
51. Scheres, S. H. Processing of structurally heterogeneous cryo-EM data in RELION. Methods Enzymol. 579, 125-157 (2016).
52. Mindell, J. A. &Grigorieff, N. Accurate determination of local defocus and specimen tilt in electron microscopy. J. Struct. Biol. 142, 334-347 (2003).
53. Tang, G. et al. EMAN2: an extensible image processing suite for electron microscopy. J. Struct. Biol. 157, 38-46 (2007).
54. Kucukelbir, A., Sigworth, F. J. &Tagare, H. D. Quantifying the local resolution of cryo-EM density maps. Nat. Methods 11, 63-65 (2014).
55. Collaborative Computational Project, N The CCP4 suite: programs for protein crystallography. Acta crystallographica. Section D, Biological crystallography 50, 760-763 (1994).
56. Emsley, P. &Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132 (2004).
57. Adams, P. D. et al. PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr. D Biol. Crystallogr. 58, 1948-1954 (2002).
58. Chen, V. B. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12-21 (2010).
59. Baker, N. A., Sept, D., Joseph, S., Holst, M. J. &McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl Acad. Sci. USA 98, 10037-10041 (2001).
60. Smart, O. S., Neduvelil, J. G., Wang, X., Wallace, B. A. &Sansom, M. S. HOLE: a program for the analysis of the pore dimensions of ion channel structural models. J. Mol. Graph. 14, 376 (1996).