Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca^(2+) ions and L-tryptophan  

作　　者：Shenglong Ling Pan Shi Sanling Liu Xianyu Meng Yingxin Zhou Wenjing Sun Shenghai Chang Xing Zhang Longhua Zhang Chaowei Shi Demeng Sun Lei Liu Changlin Tian 

机构地区：[1]Hefei National Laboratory of Physical Sciences at Microscale,Anhui Laboratory of Advanced Photonic Science and Technology,and School of Life Sciences,University of Science and Technology of China,Hefei,Anhui,230026,China [2]School of Medicine,Zhejiang University,Hangzhou,Zhejiang,310011,China [3]Tsinghua-Peking Joint Center for Life Sciences,Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology,Department of Chemistry,Tsinghua University,Beijing,100084,China [4]High Magnetic Field Laboratory,Chinese Academy of Sciences,Hefei,Anhui,230030,China [5]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China

出　　处：《Cell Research》2021年第4期383-394,共12页细胞研究（英文版）

基　　金：This work was funded by the National Natural Science Foundation of China(21825703,21778051,91753205 and 31971152);the National Key R&D Program of China(2017YFA0505400,2017YFA0505200,2016YFA0400900 and 2017YFA0505300);China Postdoctoral Science Foundation Funded Project(2017M612084);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB37000000);Dr.Sanling Liu was a recipient of Amgen Postdoc Fellowship(China)at the time when the research was conducted.

摘　　要：The human calcium-sensing receptor(CaSR)is a class C G protein-coupled receptor(GPCR)responsible for maintaining Ca^(2+)homeostasis in the blood.The general consensus is that extracellular Ca^(2+)is the principal agonist of CaSR.Aliphatic and aromatic L-amino acids,such as L-Phe and L-Trp,increase the sensitivity of CaSR towards Ca^(2+)and are considered allosteric activators.Crystal structures of the extracellular domain(ECD)of CaSR dimer have demonstrated Ca^(2+)and L-Trp binding sites and conformational changes of the ECD upon Ca^(2+)/L-Trp binding.However,it remains to be understood at the structural level how Ca^(2+)/L-Trp binding to the ECD leads to conformational changes in transmembrane domains(TMDs)and consequent CaSR activation.Here,we determined the structures of full-length human CaSR in the inactive state,Ca^(2+)-or L-Trp-bound states,and Ca^(2+)/L-Trp-bound active state using single-particle cryo-electron microscopy.Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap(VFT)domain of CaSR,bringing the receptor into an intermediate active state.Ca^(2+)binding relays the conformational changes from the VFT domains to the TMDs,consequently inducing close contact between the two TMDs of dimeric CaSR,activating the receptor.Importantly,our structural and functional studies reveal that Ca^(2+)ions and L-Trp activate CaSR cooperatively.Amino acids are not able to activate CaSR alone,but can promote the receptor activation in the presence of Ca^(2+).Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

关 键 词：ACTIVATION HOMEOSTASIS bringing 

分 类 号：R36[医药卫生—病理学]