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Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution

✍ Scribed by Céline Schalk-Hihi; Carsten Schubert; Richard Alexander; Shariff Bayoumy; Jose C. Clemente; Ingrid Deckman; Renee L. DesJarlais; Keli C. Dzordzorme; Christopher M. Flores; Bruce Grasberger; James K. Kranz; Frank Lewandowski; Li Liu; Hongchang Ma; Diane Maguire; Mark J. Macielag; Mark E. McDonnell; Tara Mezzasalma Haarlander; Robyn Miller; Cindy Milligan; Charles Reynolds; Lawrence C. Kuo

Book ID
105356602
Publisher
Cold Spring Harbor Laboratory Press
Year
2011
Tongue
English
Weight
724 KB
Volume
20
Category
Article
ISSN
0961-8368

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✦ Synopsis

Abstract

A high‐resolution structure of a ligand‐bound, soluble form of human monoglyceride lipase (MGL) is presented. The structure highlights a novel conformation of the regulatory lid‐domain present in the lipase family as well as the binding mode of a pharmaceutically relevant reversible inhibitor. Analysis of the structure lacking the inhibitor indicates that the closed conformation can accommodate the native substrate 2‐arachidonoyl glycerol. A model is proposed in which MGL undergoes conformational and electrostatic changes during the catalytic cycle ultimately resulting in its dissociation from the membrane upon completion of the cycle. In addition, the study outlines a successful approach to transform membrane associated proteins, which tend to aggregate upon purification, into a monomeric and soluble form.

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