9C2F
Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '54149
This is a non-PDB format compatible entry.
Summary for 9C2F
| Entry DOI | 10.2210/pdb9c2f/pdb |
| EMDB information | 45156 |
| Descriptor | Extracellular calcium-sensing receptor, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total) |
| Functional Keywords | g-protein coupled receptor, calcium-sensing, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 217064.13 |
| Authors | |
| Primary citation | Liu, F.,Wu, C.G.,Tu, C.L.,Glenn, I.,Meyerowitz, J.,Kaplan, A.L.,Lyu, J.,Cheng, Z.,Tarkhanova, O.O.,Moroz, Y.S.,Irwin, J.J.,Chang, W.,Shoichet, B.K.,Skiniotis, G. Large library docking identifies positive allosteric modulators of the calcium-sensing receptor. Science, 385:eado1868-eado1868, 2024 Cited by PubMed Abstract: Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs. PubMed: 39298584DOI: 10.1126/science.ado1868 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
Download full validation report
