title: Structural basis for molecular recognition at serotonin receptors.
abstract: 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.
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jinming
authors.initials: J
authors.lastname: Ma
authors.forename: Huixian
authors.initials: H
authors.lastname: Wu
authors.forename: Daniel
authors.initials: D
authors.lastname: Wacker
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: X Edward
authors.initials: XE
authors.lastname: Zhou
authors.forename: Karsten
authors.initials: K
authors.lastname: Melcher
authors.forename: Chenghai
authors.initials: C
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004087:Dihydroergotamine / Q000737:chemistry / Q000378:metabolism*; D004878:Ergotamine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008238:Lysergic Acid Diethylamide / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009642:Norfenfluramine / Q000737:chemistry / Q000378:metabolism; D010869:Pindolol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D011433:Propranolol / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism*; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism
chemical_list: C470302:HTR1B protein, human; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; D009642:Norfenfluramine; D004087:Dihydroergotamine; C047975:cyanopindolol; D008238:Lysergic Acid Diethylamide; D011433:Propranolol; D010869:Pindolol; D004878:Ergotamine