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

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 MilliganCharles Reynolds, Lawrence C. Kuo

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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.

Original languageEnglish
Pages (from-to)670-683
Number of pages14
JournalProtein Science
Volume20
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

Keywords

  • Cannabinoid receptor
  • Lid-domain
  • Monoglyceride lipase
  • Protein inhibitor complex

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