Summary
PDB 2VYA deposited: 2008-07-22 modified: 2011-07-13
Title CRYSTAL STRUCTURE OF FATTY ACID AMIDE HYDROLASE CONJUGATED WITH THE DRUG-LIKE INHIBITOR PF-750
Authors Ahn, K., Bhattacharya, K., Cravatt, B.F., Everdeen, D.S., Johnson, D.S., Kamtekar, S., Liimatta, M., Mileni, M., Nugent, R.A., Pabst, B., Stevens, R.C., Wang, Z.
Method X-RAY DIFFRACTION
Structure factors resolution 2.75 rfactor 0.188 rfree 0.239
DPI 1.03 theoretical min: 0.43
Citations

The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, and antiinflammatory phenotypes but not the undesirable side effects of direct cannabinoid receptor agonists, indicating that FAAH may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing the human FAAH enzyme. Here, we address this problem by interconverting the active sites of rat and human FAAH using site-directed mutagenesis. The resulting humanized rat (h/r) FAAH protein exhibits the inhibitor sensitivity profiles of human FAAH but maintains the high-expression yield of the rat enzyme. We report a 2.75-A crystal structure of h/rFAAH complexed with an inhibitor, N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750), that shows strong preference for human FAAH. This structure offers compelling insights to explain the species selectivity of FAAH inhibitors, which should guide future drug design programs.

Proc.Natl.Acad.Sci.USA 2008 Sep; 105(35):12820- doi:10.1073/PNAS.0806121105

Cross References
Database source Identifier Description
PubMed 18753625 PNASA6
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2VYA/1 2VYA 1 dimer 0 2 7 6521