Structural Basis for Molecular Recognition at Serotonin Receptors

被引：404

作者：

Wang, Chong ^{[1
]}

Jiang, Yi ^{[1
,2
]}

Ma, Jinming ^{[1
,3
]}

Wu, Huixian ^{[1
]}

Wacker, Daniel ^{[1
]}

Katritch, Vsevolod ^{[1
]}

Han, Gye Won ^{[1
]}

Liu, Wei ^{[1
]}

Huang, Xi-Ping ^{[4
,5
]}

Vardy, Eyal ^{[4
,5
]}

McCorvy, John D. ^{[4
,5
]}

Gao, Xiang ^{[3
]}

Zhou, X. Edward ^{[3
]}

Melcher, Karsten ^{[3
]}

Zhang, Chenghai ^{[2
,3
]}

Bai, Fang ^{[6
]}

Yang, Huaiyu ^{[7
]}

Yang, Linlin ^{[7
]}

Jiang, Hualiang ^{[7
]}

Roth, Bryan L. ^{[4
,5
]}

Cherezov, Vadim ^{[1
]}

Stevens, Raymond C. ^{[1
]}

Xu, H. Eric ^{[2
,3
]}

机构：

[1] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Inst Mat Med Ctr, Van Andel Res Inst,CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[3] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA

[4] Univ N Carolina, Sch Med, Dept Pharmacol, NIMH,Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA

[5] Univ N Carolina, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA

[6] Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, State Key Lab Technol, Dept Engn Mech, Dalian 116023, Peoples R China

[7] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

SCIENCE | 2013年 / 340卷 / 6132期

关键词：

AGONIST; FENFLURAMINE; PHARMACOLOGY; MUTATION; LIGANDS; TARGETS; BINDING;

D O I：

10.1126/science.1232807

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT1B G protein-coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT2B receptor, the 5-HT1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

引用

页码：610 / 614

页数：5

共 27 条

[1] A SINGLE-POINT MUTATION INCREASES THE AFFINITY OF SEROTONIN 5-HT1D-ALPHA, 5-HT1D-BETA, 5-HT1E AND 5-HT1F RECEPTORS FOR BETA-ADRENERGIC ANTAGONISTS [J].

ADHAM, N ;

TAMM, JA ;

SALON, JA ;

VAYSSE, PJJ ;

WEINSHANK, RL ;

BRANCHEK, TA .

NEUROPHARMACOLOGY, 1994, 33 (3-4) :387-391

[2]

Ballesteros J. A., 1995, Neuroscience Methods, V25, P366, DOI [10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471]

[3] The Expanded Biology of Serotonin [J].

Berger, Miles ;

Gray, John A. ;

Roth, Bryan L. .

ANNUAL REVIEW OF MEDICINE, 2009, 60 :355-366

[4] Automated design of ligands to polypharmacological profiles [J].

Besnard, Jeremy ;

Ruda, Gian Filippo ;

Setola, Vincent ;

Abecassis, Keren ;

Rodriguiz, Ramona M. ;

Huang, Xi-Ping ;

Norval, Suzanne ;

Sassano, Maria F. ;

Shin, Antony I. ;

Webster, Lauren A. ;

Simeons, Frederick R. C. ;

Stojanovski, Laste ;

Prat, Annik ;

Seidah, Nabil G. ;

Constam, Daniel B. ;

Bickerton, G. Richard ;

Read, Kevin D. ;

Wetsel, William C. ;

Gilbert, Ian H. ;

Roth, Bryan L. ;

Hopkins, Andrew L. .

NATURE, 2012, 492 (7428) :215-+

[5] Assessment of the roles of serines 5.43(239) and 5.46(242) for binding and potency of agonist ligands at the human serotonin 5-HT2A receptor [J].

Braden, Michael R. ;

Nichols, David E. .

MOLECULAR PHARMACOLOGY, 2007, 72 (05) :1200-1209

[6] High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor [J].

Cherezov, Vadim ;

Rosenbaum, Daniel M. ;

Hanson, Michael A. ;

Rasmussen, Soren G. F. ;

Thian, Foon Sun ;

Kobilka, Tong Sun ;

Choi, Hee-Jung ;

Kuhn, Peter ;

Weis, William I. ;

Kobilka, Brian K. ;

Stevens, Raymond C. .

SCIENCE, 2007, 318 (5854) :1258-1265

[7] Valvular heart disease associated with fenfluramine-phentermine [J].

Connolly, HM ;

Crary, JL ;

McGoon, MD ;

Hensrud, DD ;

Edwards, BS ;

Edwards, WD ;

Schaff, HV .

NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (09) :581-588

[8]

Goldenberg Marvin M, 2012, P T, V37, P499

[9] Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist [J].

Haga, Kazuko ;

Kruse, Andrew C. ;

Asada, Hidetsugu ;

Yurugi-Kobayashi, Takami ;

Shiroishi, Mitsunori ;

Zhang, Cheng ;

Weis, William I. ;

Okada, Tetsuji ;

Kobilka, Brian K. ;

Haga, Tatsuya ;

Kobayashi, Takuya .

NATURE, 2012, 482 (7386) :547-U147

[10]

HOYER D, 1994, PHARMACOL REV, V46, P157

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