Conformational gating, dynamics and allostery in human monoacylglycerol lipase.

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TitleConformational gating, dynamics and allostery in human monoacylglycerol lipase.
Publication TypeJournal Article
Year of Publication2020
AuthorsTyukhtenko, S, Ma, X, Rajarshi, G, Karageorgos, I, Anderson, KW, Hudgens, JW, Guo, JJ, Nasr, ML, Zvonok, N, Vemuri, K, Wagner, G, Makriyannis, A
JournalSci Rep
Volume10
Issue1
Pagination18531
Date Published2020 10 28
ISSN2045-2322
KeywordsAllosteric Regulation, Catalysis, Humans, Kinetics, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Dynamics Simulation, Monoacylglycerol Lipases, Mutation, Mutation, Missense, Protein Conformation, Structure-Activity Relationship
Abstract

Inhibition of human Monoacylglycerol Lipase (hMGL) offers a novel approach for treating neurological diseases. The design of inhibitors, targeting active-inactive conformational transitions of the enzyme, can be aided by understanding the interplay between structure and dynamics. Here, we report the effects of mutations within the catalytic triad on structure, conformational gating and dynamics of hMGL by combining kinetics, NMR, and HDX-MS data with metadynamics simulations. We found that point mutations alter delicate conformational equilibria between active and inactive states. HDX-MS reveals regions of the hMGL that become substantially more dynamic upon substitution of catalytic acid Asp-239 by alanine. These regions, located far from the catalytic triad, include not only loops but also rigid α-helixes and β-strands, suggesting their involvement in allosteric regulation as channels for long-range signal transmission. The results identify the existence of a preorganized global communication network comprising of tertiary (residue-residue contacts) and quaternary (rigid-body contacts) networks that mediate robust, rapid intraprotein signal transmission. Catalytic Asp-239 controls hMGL allosteric communications and may be considered as an essential residue for the integration and transmission of information to enzymes' remote regions, in addition to its well-known role to facilitate Ser-122 activation. Our findings may assist in the identification of new druggable sites in hMGL.

DOI10.1038/s41598-020-75497-5
Alternate JournalSci Rep
PubMed ID33116203
PubMed Central IDPMC7595040
Grant ListR21DA045882 / DA / NIDA NIH HHS / United States
R01DA003801 / DA / NIDA NIH HHS / United States