Effects of Distal Residues Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase

Published

January 29, 2018

Author(s)

Sergiy Tyukhtenko, Girija Rajarshi, Ioannis Karageorgos, Nikolai Zvonok, Elyssia S. Gallagher, Hongwei Huang, Kiran Vemuri, Jeffrey W. Hudgens, Alexandros Makriyannis

Abstract

An understanding of how conformational dynamics modulates function and catalysis of human monoacylglycerol lipase (hMGL), an important pharmaceutical target, can facilitate the development of novel modulatory ligands. Here, we report the discovery and characterization of an allosteric, regulatory hMGL site comprised of residues Trp-289 and Leu-232 that reside over 18 Å away from the catalytic triad. These residues were identified as critical mediators of long-range communication as well as important contributors to the integrity of the hMGL structure. Nonconservative replacements of Trp-289 or Leu-232 triggered concerted motions of structurally distinct regions with a significant conformational shift toward an inactive form and dramatic loss in catalytic efficiency of the enzyme. Using a multimethod approach, we show that the dynamically relevant Trp-289 and Leu-232 residues serve as communication hubs within an allosteric protein network that controls signal propagation to the active site, and thus, regulates active-inactive interconversion of hMGL. Our findings provide new insights into the mechanism of allosteric regulation of lipase activity, in general, and may provide alternative drug design possibilities.

Citation

Nature - Scientific Reports

Pub Type

Journals

Download Paper

Local Download

Keywords

allosteric regulation, enzyme catalysis, lipase, open-closed transition, hydrogen deuterium exchange mass spectrometry

Citation

Tyukhtenko, S. , Rajarshi, G. , Karageorgos, I. , Zvonok, N. , Gallagher, E. , Huang, H. , Vemuri, K. , Hudgens, J. and Makriyannis, A. (2018), Effects of Distal Residues Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase, Nature - Scientific Reports, [online], https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=922011 (Accessed October 14, 2025)