title: Crystal structure of a soluble form of human monoglyceride lipase in complex with an inhibitor at 1.35 Å resolution.
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.
authors.affiliation: Department of Structural Biology, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, Spring House, Pennsylvania 19477, USA. cschalkh@its.jnj.com
authors.forename: Céline
authors.initials: C
authors.lastname: Schalk-Hihi
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Richard
authors.initials: R
authors.lastname: Alexander
authors.forename: Shariff
authors.initials: S
authors.lastname: Bayoumy
authors.forename: Jose C
authors.initials: JC
authors.lastname: Clemente
authors.forename: Ingrid
authors.initials: I
authors.lastname: Deckman
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Keli C
authors.initials: KC
authors.lastname: Dzordzorme
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
authors.forename: Bruce
authors.initials: B
authors.lastname: Grasberger
authors.forename: James K
authors.initials: JK
authors.lastname: Kranz
authors.forename: Frank
authors.initials: F
authors.lastname: Lewandowski
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Hongchang
authors.initials: H
authors.lastname: Ma
authors.forename: Diane
authors.initials: D
authors.lastname: Maguire
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Macielag
authors.forename: Mark E
authors.initials: ME
authors.lastname: McDonnell
authors.forename: Tara
authors.initials: T
authors.lastname: Mezzasalma Haarlander
authors.forename: Robyn
authors.initials: R
authors.lastname: Miller
authors.forename: Cindy
authors.initials: C
authors.lastname: Milligan
authors.forename: Charles
authors.initials: C
authors.lastname: Reynolds
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
mesh_terms: D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D063388:Endocannabinoids; D005989:Glycerides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases