| Structural highlights
5zhp is a 2 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Gene: | Chrm3, Chrm-3 (Buffalo rat) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ACM3_RAT] The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.[1] [2] [3]
Publication Abstract from PubMed
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.
Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists.,Liu H, Hofmann J, Fish I, Schaake B, Eitel K, Bartuschat A, Kaindl J, Rampp H, Banerjee A, Hubner H, Clark MJ, Vincent SG, Fisher JT, Heinrich MR, Hirata K, Liu X, Sunahara RK, Shoichet BK, Kobilka BK, Gmeiner P Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):12046-12050. doi:, 10.1073/pnas.1813988115. Epub 2018 Nov 7. PMID:30404914[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wess J, Maggio R, Palmer JR, Vogel Z. Role of conserved threonine and tyrosine residues in acetylcholine binding and muscarinic receptor activation. A study with m3 muscarinic receptor point mutants. J Biol Chem. 1992 Sep 25;267(27):19313-9. PMID:1527051
- ↑ Wess J, Gdula D, Brann MR. Site-directed mutagenesis of the m3 muscarinic receptor: identification of a series of threonine and tyrosine residues involved in agonist but not antagonist binding. EMBO J. 1991 Dec;10(12):3729-34. PMID:1657592
- ↑ Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO, Shaw DE, Weis WI, Wess J, Kobilka BK. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature. 2012 Feb 22;482(7386):552-6. doi: 10.1038/nature10867. PMID:22358844 doi:10.1038/nature10867
- ↑ Liu H, Hofmann J, Fish I, Schaake B, Eitel K, Bartuschat A, Kaindl J, Rampp H, Banerjee A, Hubner H, Clark MJ, Vincent SG, Fisher JT, Heinrich MR, Hirata K, Liu X, Sunahara RK, Shoichet BK, Kobilka BK, Gmeiner P. Structure-guided development of selective M3 muscarinic acetylcholine receptor antagonists. Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):12046-12050. doi:, 10.1073/pnas.1813988115. Epub 2018 Nov 7. PMID:30404914 doi:http://dx.doi.org/10.1073/pnas.1813988115
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