| Structural highlights
Function
[ACM1_HUMAN] 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. [3SIM7_DENAN] Binds irreversibly and specifically to an allosteric site of the muscarinic acetylcholine M1 receptor (CHRM1).[1] [2] [3] [4]
Publication Abstract from PubMed
Muscarinic toxins (MTs) are natural toxins produced by mamba snakes that primarily bind to muscarinic acetylcholine receptors (MAChRs) and modulate their function. Despite their similar primary and tertiary structures, MTs show distinct binding selectivity toward different MAChRs. The molecular details of how MTs distinguish MAChRs are not well understood. Here, we present the crystal structure of M1AChR in complex with MT7, a subtype-selective anti-M1AChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for M1AChR and the mechanism by which it regulates receptor function. Through in vitro engineering of MT7 finger regions that was guided by the structure, we have converted the selectivity from M1AChR toward M2AChR, suggesting that the three-finger fold is a promising scaffold for developing G protein-coupled receptor modulators.
Structure and selectivity engineering of the M1 muscarinic receptor toxin complex.,Maeda S, Xu J, N Kadji FM, Clark MJ, Zhao J, Tsutsumi N, Aoki J, Sunahara RK, Inoue A, Garcia KC, Kobilka BK Science. 2020 Jul 10;369(6500):161-167. doi: 10.1126/science.aax2517. PMID:32646996[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nasman J, Jolkkonen M, Ammoun S, Karlsson E, Akerman KE. Recombinant expression of a selective blocker of M(1) muscarinic receptors. Biochem Biophys Res Commun. 2000 May 10;271(2):435-9. PMID:10799315 doi:http://dx.doi.org/10.1006/bbrc.2000.2657
- ↑ Krajewski JL, Dickerson IM, Potter LT. Site-directed mutagenesis of m1-toxin1: two amino acids responsible for stable toxin binding to M(1) muscarinic receptors. Mol Pharmacol. 2001 Oct;60(4):725-31. PMID:11562434
- ↑ Mourier G, Dutertre S, Fruchart-Gaillard C, Menez A, Servent D. Chemical synthesis of MT1 and MT7 muscarinic toxins: critical role of Arg-34 in their interaction with M1 muscarinic receptor. Mol Pharmacol. 2003 Jan;63(1):26-35. PMID:12488533
- ↑ Nareoja K, Kukkonen JP, Rondinelli S, Toivola DM, Meriluoto J, Nasman J. Adrenoceptor activity of muscarinic toxins identified from mamba venoms. Br J Pharmacol. 2011 Sep;164(2b):538-50. doi: 10.1111/j.1476-5381.2011.01468.x. PMID:21557730 doi:http://dx.doi.org/10.1111/j.1476-5381.2011.01468.x
- ↑ Maeda S, Xu J, N Kadji FM, Clark MJ, Zhao J, Tsutsumi N, Aoki J, Sunahara RK, Inoue A, Garcia KC, Kobilka BK. Structure and selectivity engineering of the M1 muscarinic receptor toxin complex. Science. 2020 Jul 10;369(6500):161-167. doi: 10.1126/science.aax2517. PMID:32646996 doi:http://dx.doi.org/10.1126/science.aax2517
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