Article

Structure of the human smoothened receptor bound to an antitumour agent. Nature

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature (Impact Factor: 42.35). 05/2013; 497(7449). DOI: 10.1038/nature12167
Source: PubMed

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.

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    • "On the other hand, replacement of T4L by b 562 RIL in ICL3 produced a structure closer in conformation to the inactive state, although the ionic interaction was not fully formed (Liu et al., 2012). The insertion of b 562 RIL into ICL3 of the smoothened receptor has also been proposed as a reason for the lack of structural rearrangements at the cytoplasmic surface upon agonist binding (Wang et al., 2013b). Finally, comparison of the murine d-opioid receptor structure solved with an ICL3 T4L fusion (Granier et al., 2012) and the human d-opioid receptor with an N-terminal b 562 RIL fusion (Fenalti et al., 2014) shows a high degree of structural similarity, with the main deviations occurring proximal to the sites of fusion. "
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