9C2F

Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '54149

これはPDB形式変換不可エントリーです。

9C2F の概要

• エントリーDOI: 10.2210/pdb9c2f/pdb
• EMDBエントリー: 45156
• 分子名称: 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)
• 機能のキーワード: g-protein coupled receptor, calcium-sensing, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 217064.13

構造登録者

Wu, C.,Skiniotis, G. (登録日: 2024-05-30, 公開日: 2024-10-02, 最終更新日: 2025-05-28)

主引用文献

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

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: 39298584
DOI: 10.1126/science.ado1868

実験手法

ELECTRON MICROSCOPY (2.8 Å)