Structure and Selectivity Engineering of the M Muscarinic Receptor Toxin Complex

Overview

Journal Science

Specialty Science

Date 2020 Jul 11

PMID 32646996

Citations 24

Authors

Shoji Maeda

Jun Xu

Francois Marie N Kadji

Mary J Clark

Jiawei Zhao

Naotaka Tsutsumi

Junken Aoki

Roger K Sunahara

Asuka Inoue

K Christopher Garcia

Brian K Kobilka

Affiliations

Soon will be listed here.

Abstract

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 MAChR in complex with MT7, a subtype-selective anti-MAChR snake venom toxin. The structure reveals the molecular basis of the extreme subtype specificity of MT7 for MAChR 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 MAChR toward MAChR, suggesting that the three-finger fold is a promising scaffold for developing G protein-coupled receptor modulators.

Citing Articles

Synthetic GPCRs for programmable sensing and control of cell behaviour.

Kalogriopoulos N, Tei R, Yan Y, Klein P, Ravalin M, Cai B Nature. 2024; 637(8044):230-239.

PMID: 39633047 PMC: 11666456. DOI: 10.1038/s41586-024-08282-3.

Structural basis for recognition of 26RFa by the pyroglutamylated RFamide peptide receptor.

Jin S, Guo S, Xu Y, Li X, Wu C, He X Cell Discov. 2024; 10(1):58.

PMID: 38830850 PMC: 11148045. DOI: 10.1038/s41421-024-00670-3.

Analysing the effect caused by increasing the molecular volume in M1-AChR receptor agonists and antagonists: a structural and computational study.

Montejo-Lopez W, Sampieri-Cabrera R, Nicolas-Vazquez M, Aceves-Hernandez J, Razo-Hernandez R RSC Adv. 2024; 14(13):8615-8640.

PMID: 38495977 PMC: 10938299. DOI: 10.1039/d3ra07380g.

Functional characterization of three G protein-coupled acetylcholine receptors in parasitic nematode Trichinella spiralis.

Ning C, Heckmann A, Mateos-Hernandez L, Karadjian G, Simo L Int J Parasitol Drugs Drug Resist. 2023; 23:130-139.

PMID: 38043189 PMC: 10731000. DOI: 10.1016/j.ijpddr.2023.11.005.

Deep Learning Dynamic Allostery of G-Protein-Coupled Receptors.

Do H, Wang J, Miao Y JACS Au. 2023; 3(11):3165-3180.

PMID: 38034960 PMC: 10685416. DOI: 10.1021/jacsau.3c00503.

References

Fruchart-Gaillard C, Mourier G, Marquer C, Stura E, Birdsall N, Servent D . Different interactions between MT7 toxin and the human muscarinic M1 receptor in its free and N-methylscopolamine-occupied states. Mol Pharmacol. 2008; 74(6):1554-63. DOI: 10.1124/mol.108.050773. View

Lee S, Booe J, Pioszak A . Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs. Eur J Pharmacol. 2015; 763(Pt B):196-205. PMC: 4584177. DOI: 10.1016/j.ejphar.2015.05.013. View

Jerusalinsky D, Kornisiuk E, Alfaro P, Quillfeldt J, Ferreira A, Rial V . Muscarinic toxins: novel pharmacological tools for the muscarinic cholinergic system. Toxicon. 2000; 38(6):747-61. DOI: 10.1016/s0041-0101(99)00196-8. View

Liang J, Krajewski J, McCafferty J, Purkerson S, Santiago M, Strauss W . Anti-muscarinic toxins from Dendroaspis angusticeps. Toxicon. 1996; 34(11-12):1257-67. DOI: 10.1016/s0041-0101(96)00109-2. View

Bradley K, Rowan E, Harvey A . Effects of muscarinic toxins MT2 and MT7, from green mamba venom, on m1, m3 and m5 muscarinic receptors expressed in Chinese Hamster Ovary cells. Toxicon. 2003; 41(2):207-15. DOI: 10.1016/s0041-0101(02)00278-7. View

Potter L . Snake toxins that bind specifically to individual subtypes of muscarinic receptors. Life Sci. 2001; 68(22-23):2541-7. DOI: 10.1016/s0024-3205(01)01050-5. View

Servent D, Fruchart-Gaillard C . Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors. J Neurochem. 2009; 109(5):1193-202. DOI: 10.1111/j.1471-4159.2009.06092.x. View

Blanchet G, Collet G, Mourier G, Gilles N, Fruchart-Gaillard C, Marcon E . Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: case of aminergic toxins. Biochimie. 2014; 103:109-17. DOI: 10.1016/j.biochi.2014.04.009. View

Max S, Liang J, Potter L . Purification and properties of m1-toxin, a specific antagonist of m1 muscarinic receptors. J Neurosci. 1993; 13(10):4293-300. PMC: 6576394. View

10.

Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C . Muscarinic toxins. Toxicon. 2011; 58(6-7):455-63. DOI: 10.1016/j.toxicon.2011.08.004. View

11.

Rondinelli S, Nareoja K, Nasman J . Molecular conversion of muscarinic acetylcholine receptor M(5) to muscarinic toxin 7 (MT7)-binding protein. Toxins (Basel). 2011; 3(11):1393-404. PMC: 3237002. DOI: 10.3390/toxins3111393. View

12.

Max S, Liang J, Potter L . Stable allosteric binding of m1-toxin to m1 muscarinic receptors. Mol Pharmacol. 1993; 44(6):1171-5. View

13.

Dror R, Green H, Valant C, Borhani D, Valcourt J, Pan A . Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature. 2013; 503(7475):295-9. DOI: 10.1038/nature12595. View

14.

Xu J, Hu Y, Kaindl J, Risel P, Hubner H, Maeda S . Conformational Complexity and Dynamics in a Muscarinic Receptor Revealed by NMR Spectroscopy. Mol Cell. 2019; 75(1):53-65.e7. DOI: 10.1016/j.molcel.2019.04.028. View

15.

Langmead C, Christopoulos A . Functional and structural perspectives on allosteric modulation of GPCRs. Curr Opin Cell Biol. 2014; 27:94-101. DOI: 10.1016/j.ceb.2013.11.007. View

16.

Maeda S, Qu Q, Robertson M, Skiniotis G, Kobilka B . Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science. 2019; 364(6440):552-557. PMC: 7034192. DOI: 10.1126/science.aaw5188. View

17.

Olianas M, Maullu C, Adem A, Mulugeta E, Karlsson E, Onali P . Inhibition of acetylcholine muscarinic M(1) receptor function by the M(1)-selective ligand muscarinic toxin 7 (MT-7). Br J Pharmacol. 2000; 131(3):447-52. PMC: 1572361. DOI: 10.1038/sj.bjp.0703606. View

18.

Kessler P, Marchot P, Silva M, Servent D . The three-finger toxin fold: a multifunctional structural scaffold able to modulate cholinergic functions. J Neurochem. 2017; 142 Suppl 2:7-18. DOI: 10.1111/jnc.13975. View

19.

Xu J, Zhao H, Zheng Z, Wang Y, Niu Y, Wang H . Structural determinants for the interactions between muscarinic toxin 7 and muscarinic acetylcholine receptors. J Mol Recognit. 2015; 28(4):239-52. DOI: 10.1002/jmr.2438. View

20.

Ma L, Seager M, Seager M, Wittmann M, Jacobson M, Bickel D . Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. Proc Natl Acad Sci U S A. 2009; 106(37):15950-5. PMC: 2732705. DOI: 10.1073/pnas.0900903106. View