5ZK8
Crystal structure of M2 muscarinic acetylcholine receptor bound with NMS
Summary for 5ZK8
| Entry DOI | 10.2210/pdb5zk8/pdb |
| Related | 5XB9 5XBA 5XBB |
| Descriptor | Muscarinic acetylcholine receptor M2,Redesigned apo-cytochrome b562,Muscarinic acetylcholine receptor M2, N-methyl scopolamine (3 entities in total) |
| Functional Keywords | gpcr crystallography, membrane protein-inhibitor complex, membrane protein/inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 47541.48 |
| Authors | 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. (deposition date: 2018-03-23, release date: 2018-11-21, Last modification date: 2024-10-30) |
| Primary citation | 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 Cited by 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: 30420692DOI: 10.1038/s41589-018-0152-y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
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