3PE6

Crystal Structure of a soluble form of human MGLL in complex with an inhibitor

Summary for 3PE6

• Entry DOI: 10.2210/pdb3pe6/pdb
• Related: 3HJU 3JW8 3JWE
• Descriptor: Monoglyceride lipase, (2-cyclohexyl-1,3-benzoxazol-6-yl){3-[4-(pyrimidin-2-yl)piperazin-1-yl]azetidin-1-yl}methanone (3 entities in total)
• Functional Keywords: alpha-beta hydrolase fold, lipase, 2-arachidonyl-glycerol, membrane associated, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 33637.67

Authors

Schubert, C.,Schalk-Hih, C. (deposition date: 2010-10-25, release date: 2011-03-02, Last modification date: 2023-09-06)

Primary citation

Schalk-Hihi, C.,Schubert, C.,Alexander, R.,Bayoumy, S.,Clemente, J.C.,Deckman, I.,DesJarlais, R.L.,Dzordzorme, K.C.,Flores, C.M.,Grasberger, B.,Kranz, J.K.,Lewandowski, F.,Liu, L.,Ma, H.,Maguire, D.,Macielag, M.J.,McDonnell, M.E.,Mezzasalma Haarlander, T.,Miller, R.,Milligan, C.,Reynolds, C.,Kuo, L.C.
Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 A resolution.
Protein Sci., 20:670-683, 2011

PubMed 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.

PubMed: 21308848
DOI: 10.1002/pro.596

Experimental method

X-RAY DIFFRACTION (1.35 Å)