3K83

Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

Summary for 3K83

• Entry DOI: 10.2210/pdb3k83/pdb
• Related: 2wj1 2wj2 3K84 3k7f
• Descriptor: Fatty-acid amide hydrolase 1, 6-[2-(3-biphenyl-4-ylpropanoyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: faah, oxazole, conjugate, covalent modification, hydrolase, membrane, transmembrane, monotopic, fatty acid, serine hydrolase, endocannabinoid, reversible inhibitor.
• Biological source: Rattus norvegicus (rat)
• Cellular location: Endoplasmic reticulum membrane; Single-pass membrane protein: P97612
• Total number of polymer chains: 2
• Total formula weight: 127241.94

Authors

Mileni, M.,Stevens, R.C.,Boger, D.L. (deposition date: 2009-10-13, release date: 2009-12-01, Last modification date: 2024-11-06)

Primary citation

Mileni, M.,Garfunkle, J.,Ezzili, C.,Kimball, F.S.,Cravatt, B.F.,Stevens, R.C.,Boger, D.L.
X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase.
J.Med.Chem., 53:230-240, 2010

PubMed Abstract: Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.

PubMed: 19924997
DOI: 10.1021/jm9012196

Experimental method

X-RAY DIFFRACTION (2.251 Å)