Structure of the human smoothened receptor bound to an antitumour agent.
Structure of the human smoothened receptor bound to an antitumour agent.
复制标题
与抗肿瘤药物结合的人平滑受体的结构。
作者：
smoothened（SMO）受体是刺猬（Hh）信号通路中的关键信号转导因子，它既负责维持正常的胚胎发育，又与癌症发生有关。SMO受体被归类为卷曲蛋白类（F类）G蛋白偶联受体（GPCR），尽管经典的Hh信号通路涉及转录因子Gli，且其与A类GPCR的序列相似性低于10%。在此我们报道了分辨率为2.5 Å的人源SMO受体跨膜结构域与小分子拮抗剂LY2940680结合的晶体结构。尽管SMO受体具有七次跨膜螺旋（7TM）折叠结构，但A类GPCR中大多数保守的基序缺失，并且该结构揭示了由四个二硫键稳定的长胞外环的异常复杂排列。配体结合在7TM束的胞外端，并与环形成广泛的接触。
The smoothened (SMO) receptor, a key signal transducer in the Hedgehog (Hh) signaling pathway is both responsible for the maintenance of normal embryonic development and implicated in carcinogenesis. The SMO receptor is classified as a class Frizzled (class F) G protein-coupled receptor (GPCR), although the canonical Hh signaling pathway involves the transcription factor Gli and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure at 2.5 Å resolution of the transmembrane domain of the human SMO receptor bound to the small molecule antagonist LY2940680. Although the SMO receptor shares the seven transmembrane helical (7TM) fold, most conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulfide bonds. The ligand binds at the extracellular end of the 7TM bundle and forms extensive contacts with the loops.