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 Raymond C. Stevens  

 
Nature(2013) doi:10.1038/nature12167 Received15 January 2013 Accepted12 April 2013 Published online01 May 2013

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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 smallmolecule antagonist LY2940680 at 2.5Å 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.