EMD-45127

Composite map
Single-particle
2.8 Å
EMD-45127 Deposition: 29/05/2024
Map released: 02/10/2024
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-45127

Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218

EMD-45127

Composite map
Single-particle
2.8 Å
EMD-45127 Deposition: 29/05/2024
Map released: 02/10/2024
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: Calcium-sensing receptor bound to compound '6218
Fitted models: 9c1p (Avg. Q-score: 0.568)

Deposition Authors: Wu C, Skiniotis G
Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.
Liu F , Wu CG , Tu CL, Glenn I , Meyerowitz J , Kaplan AL , Lyu J , Cheng Z, Tarkhanova OO , Moroz YS , Irwin JJ , Chang W , Shoichet BK , Skiniotis G
(2024) Science , 385 , eado1868 - eado1868
PUBMED: 39298584
DOI: doi:10.1126/science.ado1868
ISSN: 1095-9203
ASTM: SCIEAS
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.