Summary
PDB 3LJ6 deposited: 2010-01-25 modified: 2011-12-14
Title 3D-CRYSTAL STRUCTURE OF HUMANIZED-RAT FATTY ACID AMIDE HYDROLASE (FAAH) CONJUGATED WITH THE DRUG-LIKE UREA INHIBITOR PF-3845 at 2.42A RESOLUTION
Authors Benson, T.E., Cravatt, B.F., Kamtekar, S., Mileni, M., Stevens, R.C., Wood, D.C.
Method X-RAY DIFFRACTION
Structure factors resolution 2.42 rfactor 0.1606 rfree 0.1995
DPI 0.49 theoretical min: 0.26
Related PDB Entries 3LJ7
Citations

The endocannabinoid system regulates a wide range of physiological processes including pain, inflammation, and cognitive/emotional states. URB597 is one of the best characterized covalent inhibitors of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH). Here, we report the structure of the FAAH-URB597 complex at 2.3 A resolution. The structure provides insights into mechanistic details of enzyme inactivation and experimental evidence of a previously uncharacterized active site water molecule that likely is involved in substrate deacylation. This water molecule is part of an extensive hydrogen-bonding network and is coordinated indirectly to residues lining the cytosolic port of the enzyme. In order to corroborate our hypothesis concerning the role of this water molecule in FAAH's catalytic mechanism, we determined the structure of FAAH conjugated to a urea-based inhibitor, PF-3845, to a higher resolution (2.4 A) than previously reported. The higher-resolution structure confirms the presence of the water molecule in a virtually identical location in the active site. Examination of the structures of serine hydrolases that are non-homologous to FAAH, such as elastase, trypsin, or chymotrypsin, shows a similarly positioned hydrolytic water molecule and suggests a functional convergence between the amidase signature enzymes and serine proteases.

J.Mol.Biol. 2010 Jul; 400(4):743-754 doi:10.1016/j.jmb.2010.05.034

Cross References
Database source Identifier Description
PubMed 20493882 JMOBAK
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3LJ6/1 3LJ6 1 monomer 0 1 2 3666
3LJ6/2 3LJ6 2 monomer 0 1 1 3752
3LJ6/3 3LJ6 3 dimer 0 2 3 7418