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TitleStructural insights into the activation of human calcium-sensing receptor.
Journal, issue, pagesElife, Vol. 10, Year 2021
Publish dateSep 1, 2021
AuthorsXiaochen Chen / Lu Wang / Qianqian Cui / Zhanyu Ding / Li Han / Yongjun Kou / Wenqing Zhang / Haonan Wang / Xiaomin Jia / Mei Dai / Zhenzhong Shi / Yuying Li / Xiyang Li / Yong Geng /
PubMed AbstractHuman calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and ...Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca ions and L-amino acid leading to the activation of the receptor.
External linksElife / PubMed:34467854 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 6.0 Å
Structure data

30996

7e6t

EMDB-30996, PDB-7e6t:
Structural insights into the activation of human calcium-sensing receptor
Method: EM (single particle) / Resolution: 3.0 Å

30997

7e6u

EMDB-30997, PDB-7e6u:
the complex of inactive CaSR and NB2D11
Method: EM (single particle) / Resolution: 6.0 Å

Chemicals

ChemComp-PO4:
PHOSPHATE ION

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-TCR:
CYCLOMETHYLTRYPTOPHAN

Source
  • homo sapiens (human)
  • escherichia phage ecszw-2 (virus)
KeywordsSTRUCTURAL PROTEIN / G-protein-coupled receptor (GPCR); Calcium-sensing receptor (CaSR); cryo-electron microscopy (cryo-EM); calcium ions; nanobody

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