Skip to main content
U.S. flag

An official website of the United States government

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.

Conformational gating, dynamics and allostery in human monoacylglycerol lipase



Sergiy Tyukhtenko, Girija Rajarshi, Ioannis Karageorgos, Nikolai Zvonok, Kiran Vemuri, Jeffrey W. Hudgens, Xiaoyu Ma, Mahmoud L. Nasr, Alexandros Makriyannis, Kyle Anderson, Jason J. Guo, Gerhard Wagner


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.
Scientific Reports


allosteric regulation, catalytic triad, human Monoacylglycerol Lipase, Hydrogen-deuterium exchange, mutagenesis, NMR


Tyukhtenko, S. , Rajarshi, G. , Karageorgos, I. , Zvonok, N. , Vemuri, K. , Hudgens, J. , Ma, X. , Nasr, M. , Makriyannis, A. , Anderson, K. , Guo, J. and Wagner, G. (2020), Conformational gating, dynamics and allostery in human monoacylglycerol lipase, Scientific Reports, [online], (Accessed May 30, 2024)


If you have any questions about this publication or are having problems accessing it, please contact

Created October 27, 2020, Updated October 12, 2021