title: Structure of the human smoothened receptor bound to an antitumour agent.
abstract: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Chong
authors: C
authors: Wang
authors: Huixian
authors: H
authors: Wu
authors: Vsevolod
authors: V
authors: Katritch
authors: Gye Won
authors: GW
authors: Han
authors: Xi-Ping
authors: XP
authors: Huang
authors: Wei
authors: W
authors: Liu
authors: Fai Yiu
authors: FY
authors: Siu
authors: Bryan L
authors: BL
authors: Roth
authors: Vadim
authors: V
authors: Cherezov
authors: Raymond C
authors: RC
authors: Stevens
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D051157:Frizzled Receptors / Q000737:chemistry / Q000145:classification; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010793:Phthalazines / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D000072086:Smoothened Receptor; D040681:Structural Homology, Protein
chemical_list: D000970:Antineoplastic Agents; D004220:Disulfides; D051157:Frizzled Receptors; C581399:LY2940680; D008024:Ligands; D010793:Phthalazines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor
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