Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 51, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2115849118
Keywords
calcium-sensing receptor; cryo-EM structure; allosteric modulation; activation mechanism; symmetry
Categories
Funding
- National University of Singapore
- Agency for Science, Technology and Research Singapore
- Simons Foundation [SF349247]
- NIH [R35GM141871, R01GM29169, P41GM116799, R01GM107462, GM103310]
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The study reveals the structural insights of the human extracellular calcium-sensing receptor in the presence and absence of allosteric modulators, showing that activation of the receptor requires a break in the transmembrane 6 helix. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain to stabilize distinct conformations of key residues on the TM6 helix, influencing receptor activity.
The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ 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.
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