PDB 3K83 deposited: 2009-10-13 modified: 2010-01-19
Title Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase
Authors Boger, D.L., Cravatt, B.F., Ezzili, C., Garfunkle, J., Kimball, F.S., Mileni, M., Stevens, R.C.
Structure factors resolution 2.251 rfactor 0.1439 rfree 0.1983
DPI 0.53 theoretical min: 0.21
Related PDB Entries 3K7F 3K84

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.

J.Med.Chem. 2010 Jan; 53(1):230-240 doi:10.1021/jm9012196

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1156770
PubMed 19924997 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3K83/1 3K83 1 dimer 0 2 4 7470