Structure of the human smoothened receptor bound to an antitumour agent

作者：Wei Liu, Vsevolod Katritch, Bryan L. Roth, Chong Wang, Raymond C. Stevens, Fai Siu, Xi‐Ping Huang, Vadim Cherezov, Gye Won Han, Huixian Wu · 发表于：UNC Libraries · 年份：2020 · DOI：10.17615/9b29-5258 · 被引用次数：12 · 研究领域：Estrogen and related hormone effects、Receptor Mechanisms and Signaling、Chemical Synthesis and Analysis

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.