Wang Chong, Wu Huixian, Evron Tama, Vardy Eyal, Han Gye Won, Huang Xi-Ping, Hufeisen Sandy J, Mangano Thomas J, Urban Dan J, Katritch Vsevolod, Cherezov Vadim, Caron Marc G, Roth Bryan L, Stevens Raymond C
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nat Commun. 2014 Jul 10;5:4355. doi: 10.1038/ncomms5355.
The Smoothened receptor (SMO) mediates signal transduction in the hedgehog pathway, which is implicated in normal development and carcinogenesis. SMO antagonists can suppress the growth of some tumours; however, mutations at SMO have been found to abolish their antitumour effects, a phenomenon known as chemoresistance. Here we report three crystal structures of human SMO bound to the antagonists SANT1 and Anta XV, and the agonist, SAG1.5, at 2.6-2.8 Å resolution. The long and narrow cavity in the transmembrane domain of SMO harbours multiple ligand binding sites, where SANT1 binds at a deeper site as compared with other ligands. Distinct interactions at D473(6.54f) elucidated the structural basis for the differential effects of chemoresistance mutations on SMO antagonists. The agonist SAG1.5 induces a conformational rearrangement of the binding pocket residues, which could contribute to SMO activation. Collectively, these studies reveal the structural basis for the modulation of SMO by small molecules.
平滑受体（SMO）介导刺猬信号通路中的信号转导，该通路与正常发育和肿瘤发生有关。SMO拮抗剂可抑制某些肿瘤的生长；然而，已发现SMO处的突变会消除其抗肿瘤作用，这一现象称为化学抗性。在此，我们报告了人源SMO与拮抗剂SANT1和Anta XV以及激动剂SAG1.5结合的三种晶体结构，分辨率为2.6-2.8Å。SMO跨膜结构域中狭长的腔容纳多个配体结合位点，与其他配体相比，SANT1在更深的位点结合。D473（6.54f）处的不同相互作用阐明了化学抗性突变对SMO拮抗剂产生不同影响的结构基础。激动剂SAG1.5诱导结合口袋残基的构象重排，这可能有助于SMO的激活。总体而言，这些研究揭示了小分子调节SMO的结构基础。
