5ZKC

Crystal structure of rationally thermostabilized M2 muscarinic acetylcholine receptor bound with NMS

5ZKC の概要

• エントリーDOI: 10.2210/pdb5zkc/pdb
• 関連するPDBエントリー: 5ZK3 5ZK8 5ZKB
• 分子名称: Muscarinic acetylcholine receptor M2,Apo-cytochrome b562,Muscarinic acetylcholine receptor M2, N-methyl scopolamine (3 entities in total)
• 機能のキーワード: gpcr crystallography, rationally thermostabilized mutant, membrane protein-inhibitor complex, membrane protein/inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47611.59

構造登録者

Suno, R.,Maeda, S.,Yasuda, S.,Yamashita, K.,Hirata, K.,Horita, S.,Tawaramoto, M.S.,Tsujimoto, H.,Murata, T.,Kinoshita, M.,Yamamoto, M.,Kobilka, B.K.,Iwata, S.,Kobayashi, T. (登録日: 2018-03-23, 公開日: 2018-11-21, 最終更新日: 2024-10-23)

主引用文献

Suno, R.,Lee, S.,Maeda, S.,Yasuda, S.,Yamashita, K.,Hirata, K.,Horita, S.,Tawaramoto, M.S.,Tsujimoto, H.,Murata, T.,Kinoshita, M.,Yamamoto, M.,Kobilka, B.K.,Vaidehi, N.,Iwata, S.,Kobayashi, T.
Structural insights into the subtype-selective antagonist binding to the M2muscarinic receptor
Nat. Chem. Biol., 14:1150-1158, 2018

PubMed Abstract: Human muscarinic receptor M is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M receptors compared to M receptors leads to subtype selectivity of AF-DX 384.

PubMed: 30420692
DOI: 10.1038/s41589-018-0152-y

実験手法

X-RAY DIFFRACTION (2.3 Å)