5ZHP

M3 muscarinic acetylcholine receptor in complex with a selective antagonist

5ZHP の概要

• エントリーDOI: 10.2210/pdb5zhp/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900001
• 分子名称: Muscarinic acetylcholine receptor M3,Endolysin,Endolysin,Muscarinic acetylcholine receptor M3, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, TETRAETHYLENE GLYCOL, ... (6 entities in total)
• 機能のキーワード: g protein coupled receptor, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97646.19

構造登録者

Liu, H.,Hofmann, J.,Fish, I.,Schaake, B.,Eitel, K.,Bartuschat, A.,Kaindl, J.,Rampp, H.,Banerjee, A.,Hubner, H.,Clark, M.J.,Vincent, S.G.,Fisher, J.,Heinrich, M.,Hirata, K.,Liu, X.,Sunahara, R.K.,Shoichet, B.K.,Kobilka, B.K.,Gmeiner, P. (登録日: 2018-03-13, 公開日: 2018-11-28, 最終更新日: 2024-11-20)

主引用文献

Liu, H.,Hofmann, J.,Fish, I.,Schaake, B.,Eitel, K.,Bartuschat, A.,Kaindl, J.,Rampp, H.,Banerjee, A.,Hubner, H.,Clark, M.J.,Vincent, S.G.,Fisher, J.T.,Heinrich, M.R.,Hirata, K.,Liu, X.,Sunahara, R.K.,Shoichet, B.K.,Kobilka, B.K.,Gmeiner, P.
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists
Proc. Natl. Acad. Sci. U.S.A., 115:12046-12050, 2018

PubMed Abstract: Drugs that treat chronic obstructive pulmonary disease by antagonizing the M3 muscarinic acetylcholine receptor (M3R) have had a significant effect on health, but can suffer from their lack of selectivity against the M2R subtype, which modulates heart rate. Beginning with the crystal structures of M2R and M3R, we exploited a single amino acid difference in their orthosteric binding pockets using molecular docking and structure-based design. The resulting M3R antagonists had up to 100-fold selectivity over M2R in affinity and over 1,000-fold selectivity in vivo. The crystal structure of the M3R-selective antagonist in complex with M3R corresponded closely to the docking-predicted geometry, providing a template for further optimization.

PubMed: 30404914
DOI: 10.1073/pnas.1813988115

実験手法

X-RAY DIFFRACTION (3.1 Å)