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

Protein Sci. 2011 Feb 3. doi: 10.1002/pro.596. [Epub ahead of print]

Schalk-Hihi C, Schubert C, Alexander R, Bayoumy S, Clemente JC, Deckman I, Desjarlais RL, Dzordzorme KC, Flores CM, Grasberger B, Kranz JK, Lewandowski F, Liu L, Ma H, Maguire D, Macielag MJ, McDonnell ME, Haarlander TM, Miller R, Milligan C, Reynolds C, Kuo LC.

Departments of Structural Biology, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477. cschalkh@its.jnj.com.

A high-resolution structure of a ligand-bound, soluble form of human monoglyceride lipase 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 monoglyceride lipase 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.

Copyright © 2011 The Protein Society.PMID: 21308848 [PubMed - as supplied by publisher]

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