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Structure paper

TitleSymmetric activation and modulation of the human calcium-sensing receptor.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 118, Issue 51, Year 2021
Publish dateDec 21, 2021
AuthorsJinseo Park / Hao Zuo / Aurel Frangaj / Ziao Fu / Laura Y Yen / Zhening Zhang / Lidia Mosyak / Vesna N Slavkovich / Jonathan Liu / Kimberly M Ray / Baohua Cao / Francesca Vallese / Yong Geng / Shaoxia Chen / Robert Grassucci / Venkata P Dandey / Yong Zi Tan / Edward Eng / Yeji Lee / Brian Kloss / Zheng Liu / Wayne A Hendrickson / Clinton S Potter / Bridget Carragher / Joseph Graziano / Arthur D Conigrave / Joachim Frank / Oliver B Clarke / Qing R Fan /
PubMed AbstractThe human extracellular calcium-sensing (CaS) receptor controls plasma Ca levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS ...The human extracellular calcium-sensing (CaS) receptor controls plasma Ca levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.
External linksProc Natl Acad Sci U S A / PubMed:34916296 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 5.9 Å
Structure data

25143

7sil

EMDB-25143, PDB-7sil:
Structure of positive allosteric modulator-bound active human calcium-sensing receptor
Method: EM (single particle) / Resolution: 2.7 Å

25144

7sim

EMDB-25144, PDB-7sim:
Structure of positive allosteric modulator-free active human calcium-sensing receptor
Method: EM (single particle) / Resolution: 2.7 Å

25145

7sin

EMDB-25145, PDB-7sin:
Structure of negative allosteric modulator-bound inactive human calcium-sensing receptor
Method: EM (single particle) / Resolution: 5.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-TCR:
CYCLOMETHYLTRYPTOPHAN

ChemComp-PO4:
PHOSPHATE ION / Phosphate

ChemComp-CA:
Unknown entry

ChemComp-9IG:
3-(2-chlorophenyl)-N-[(1R)-1-(3-methoxyphenyl)ethyl]propan-1-amine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-YP1:
2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile / antagonist, hormone*YM / NPS-2143

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / calcium-sensing receptor / cryo-EM structure / allosteric modulation / activation mechanism / symmetry

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