2VYA: Crystal Structure Of Fatty Acid Amide Hydrolase Conjugated With The Drug-Like Inhibitor Pf-750

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.
PDB ID: 2VYADownload
MMDB ID: 66576
PDB Deposition Date: 2008/7/22
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2.75  Å
Source Organism:
Similar Structures:
Biological Unit for 2VYA: dimeric; determined by software (PQS)
Molecular Components in 2VYA
Label Count Molecule
Proteins (2 molecules)
Fatty-acid Amide Hydrolase 1(Gene symbol: Faah)
Molecule annotation
Chemicals (7 molecules)
Molecule information is not avaliable.
* Click molecule labels to explore molecular sequence information.

Citing MMDB