6OL9
Structure of the M5 muscarinic acetylcholine receptor (M5-T4L) bound to tiotropium
Summary for 6OL9
| Entry DOI | 10.2210/pdb6ol9/pdb |
| Descriptor | Muscarinic acetylcholine receptor M5, T4 Lysozyme fusion, OLEIC ACID, (1R,2R,4S,5S,7S)-7-{[hydroxy(dithiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0~2,4~]nonane, ... (6 entities in total) |
| Functional Keywords | gpcr inhibitor complex, membrane protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 56733.95 |
| Authors | Vuckovic, Z.,Christopoulos, A.,Thal, D.M. (deposition date: 2019-04-16, release date: 2019-12-11, Last modification date: 2023-10-11) |
| Primary citation | Vuckovic, Z.,Gentry, P.R.,Berizzi, A.E.,Hirata, K.,Varghese, S.,Thompson, G.,van der Westhuizen, E.T.,Burger, W.A.C.,Rahmani, R.,Valant, C.,Langmead, C.J.,Lindsley, C.W.,Baell, J.B.,Tobin, A.B.,Sexton, P.M.,Christopoulos, A.,Thal, D.M. Crystal structure of the M5muscarinic acetylcholine receptor. Proc.Natl.Acad.Sci.USA, 116:26001-26007, 2019 Cited by PubMed Abstract: The human M muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all 5 mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies, together with chimeric swaps between the extracellular regions of the M and M mAChRs, provided structural insight into kinetic selectivity, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective drugs. PubMed: 31772027DOI: 10.1073/pnas.1914446116 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.541 Å) |
Structure validation
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