Crystal structure of the Frizzled 4 receptor in a ligand-free state

作     者：Yang, Shifan Wu, Yiran Xu, Ting-Hai de Waal, Parker W. He, Yuanzheng Pu, Mengchen Chen, Yuxiang DeBruine, Zachary J. Zhang, Bingjie Zaidi, Saheem A. Popov, Petr Guo, Yu Han, Gye Won Lu, Yang Suino-Powell, Kelly Dong, Shaowei Harikumar, Kaleeckal G. Miller, Laurence J. Katritch, Vsevolod Xu, H. Eric Shui, Wenqing Stevens, Raymond C. Melcher, Karsten Zhao, Suwen Xu, Fei 

作者机构：ShanghaiTech Univ iHuman Inst Shanghai Peoples R China Van Andel Res Inst Innovat & Integrat Program Ctr Canc & Cell Biol Grand Rapids MI USA Harbin Inst Technol Sch Life Sci & Technol Ctr Life Sci Harbin Heilongjiang Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai Peoples R China Univ Chinese Acad Sci Beijing Peoples R China Univ Southern Calif Dept Biol Sci Bridge Inst Los Angeles CA 90089 USA Univ Southern Calif Dept Chem Bridge Inst Los Angeles CA 90089 USA Moscow Inst Phys & Technol Dolgoprudnyi Russia Mayo Clin Dept Mol Pharmacol & Expt Therapeut Scottsdale AZ USA Chinese Acad Sci Shanghai Inst Mat Med VARI SIMM Ctr Key Lab Receptor Res Shanghai Peoples R China Chinese Acad Sci Shanghai Inst Mat Med Ctr Struct & Funct Drug Targets Shanghai Peoples R China 

出 版 物：《NATURE》 (自然)

年 卷 期：2018年第560卷第7720期

页      面：666-+页

核心收录：

学科分类：07[理学] 08[工学] 

基　　金：National Natural Science Foundation (NSF) of China National Key Research and Development Program of China [2018YFA0507004, 2016YCF0905902] NSF of Shanghai [16ZR1448500] Russian Foundation for Basic Research [RFBR 18-34-00990] Shanghai Municipal Government, ShanghaiTech University 

主　　题：Cell signalling X-ray crystallography 

摘      要：Frizzled receptors (FZDs) are class-F G-protein-coupled receptors (GPCRs) that function in Wnt signalling and are essential for developing and adult organisms(1,2). As central mediators in this complex signalling pathway, FZDs serve as gatekeeping proteins both for drug intervention and for the development of probes in basic and in therapeutic research. Here we present an atomic-resolution structure of the human Frizzled 4 receptor (FZD4) transmembrane domain in the absence of a bound ligand. The structure reveals an unusual transmembrane architecture in which helix VI is short and tightly packed, and is distinct from all other GPCR structures reported so far. Within this unique transmembrane fold is an extremely narrow and highly hydrophilic pocket that is not amenable to the binding of traditional GPCR ligands. We show that such a pocket is conserved across all FZDs, which may explain the long-standing difficulties in the development of ligands for these receptors. Molecular dynamics simulations on the microsecond timescale and mutational analysis uncovered two coupled, dynamic kinks located at helix VII that are involved in FZD4 activation. The stability of the structure in its ligand-free form, an unfavourable pocket for ligand binding and the two unusual kinks on helix VII suggest that FZDs may have evolved a novel ligand-recognition and activation mechanism that is distinct from that of other GPCRs.