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Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution
Author(s) -
SchalkHihi Céline,
Schubert Carsten,
Alexander Richard,
Bayoumy Shariff,
Clemente Jose C.,
Deckman Ingrid,
DesJarlais Renee L.,
Dzordzorme Keli C.,
Flores Christopher M.,
Grasberger Bruce,
Kranz James K.,
Lewandowski Frank,
Liu Li,
Ma Hongchang,
Maguire Diane,
Macielag Mark J.,
McDonnell Mark E.,
Mezzasalma Haarlander Tara,
Miller Robyn,
Milligan Cindy,
Reynolds Charles,
Kuo Lawrence C.
Publication year - 2011
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.596
Subject(s) - chemistry , lipase , monomer , monoglyceride , hydrolase , ligand (biochemistry) , stereochemistry , dissociation (chemistry) , protein structure , crystallography , biophysics , biochemistry , enzyme , organic chemistry , biology , receptor , fatty acid , polymer
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.