PDBsum entry 7dtu

Membrane protein

PDB id: 7dtu

Contents

Protein chains

778 a.a.

Ligands

NAG-NAG ×4

TRP ×2

NAG ×6

PDB id:

7dtu

Name:

Membrane protein

Title:

Human calcium-sensing receptor bound with l-trp

Structure:

Extracellular calcium-sensing receptor. Chain: a, b. Synonym: hcasr,parathyroid cell calcium-sensing receptor 1,pcar1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: casr, gprc2a, pcar1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Authors:

S.L.Ling,C.L.Tian,P.Shi,S.L.Liu,X.Y.Meng,L.Liu,D.M.Sun,C.W.Shi

Key ref:

S.Ling et al. (2021). Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca²⁺ ions and L-tryptophan. Cell Res, 31, 383-394. PubMed id: 33603117 DOI: 10.1038/s41422-021-00474-0

Date:

06-Jan-21 Release date: 10-Mar-21

Protein chains

P41180  (CASR_HUMAN) -  Extracellular calcium-sensing receptor from Homo sapiens

Seq: 1078 a.a.

Struc: 778 a.a.

DOI no: 10.1038/s41422-021-00474-0

Cell Res 31:383-394 (2021)

PubMed id: 33603117

Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca²⁺ ions and L-tryptophan.

S.Ling, P.Shi, S.Liu, X.Meng, Y.Zhou, W.Sun, S.Chang, X.Zhang, L.Zhang, C.Shi, D.Sun, L.Liu, C.Tian.

ABSTRACT

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca²⁺ homeostasis in the blood. The general consensus is that extracellular Ca²⁺ 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 Ca²⁺ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca²⁺ and L-Trp binding sites and conformational changes of the ECD upon Ca²⁺/L-Trp binding. However, it remains to be understood at the structural level how Ca²⁺/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, Ca²⁺- or L-Trp-bound states, and Ca²⁺/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. Ca²⁺ 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 Ca²⁺ 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 Ca²⁺. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.