Structure of the human smoothened receptor bound to an antitumour agent

Chong Wang, Huixian Wu, Vsevolod Katritch, Gye Won Han, Xi-Ping Huang, Wei Liu, Fai Yiu Siu, Bryan L. Roth, Vadim Cherezov and Raymond C. Stevens ()
Additional contact information
Chong Wang: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Huixian Wu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Vsevolod Katritch: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Gye Won Han: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Xi-Ping Huang: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA
Wei Liu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Fai Yiu Siu: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Bryan L. Roth: National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina Chapel Hill Medical School, 4072 Genetic Medicine Building, Chapel Hill, North Carolina 27514, USA
Vadim Cherezov: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
Raymond C. Stevens: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

Nature, 2013, vol. 497, issue 7449, 338-343

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12167

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