5ZHP

M3 muscarinic acetylcholine receptor in complex with a selective antagonist

Summary for 5ZHP

• Entry DOI: 10.2210/pdb5zhp/pdb
• Related PRD ID: PRD_900001
• Descriptor: Muscarinic acetylcholine receptor M3,Endolysin,Endolysin,Muscarinic acetylcholine receptor M3, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, TETRAETHYLENE GLYCOL, ... (6 entities in total)
• Functional Keywords: g protein coupled receptor, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 97646.19

Authors

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. (deposition date: 2018-03-13, release date: 2018-11-28, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.1 Å)