7M3E
Asymmetric Activation of the Calcium Sensing Receptor Homodimer
Summary for 7M3E
| Entry DOI | 10.2210/pdb7m3e/pdb |
| EMDB information | 23652 |
| Descriptor | Extracellular calcium-sensing receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-chloro-6-[(2R)-2-hydroxy-3-{[2-methyl-1-(naphthalen-2-yl)propan-2-yl]amino}propoxy]benzonitrile, ... (7 entities in total) |
| Functional Keywords | gpcr, calcium sensing receptor, negative allosteric modulator, family c gpcr, membrane protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 207482.71 |
| Authors | Gao, Y.,Robertson, M.J.,Zhang, C.,Meyerowitz, J.G.,Panova, O.,Skiniotis, G. (deposition date: 2021-03-18, release date: 2021-06-30, Last modification date: 2024-11-20) |
| Primary citation | Gao, Y.,Robertson, M.J.,Rahman, S.N.,Seven, A.B.,Zhang, C.,Meyerowitz, J.G.,Panova, O.,Hannan, F.M.,Thakker, R.V.,Brauner-Osborne, H.,Mathiesen, J.M.,Skiniotis, G. Asymmetric activation of the calcium-sensing receptor homodimer. Nature, 595:455-459, 2021 Cited by PubMed Abstract: The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders. CaSR is a family C G-protein-coupled receptor that functions as an obligate homodimer, with each protomer composed of a Ca-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor. PubMed: 34194040DOI: 10.1038/s41586-021-03691-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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