2WAP

3D-crystal structure of humanized-rat fatty acid amide hydrolase (FAAH) conjugated with the drug-like urea inhibitor PF-3845

Summary for 2WAP

• Entry DOI: 10.2210/pdb2wap/pdb
• Related: 1MT5 2VYA
• Descriptor: FATTY-ACID AMIDE HYDROLASE 1, 4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzyl)piperidine-1-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: fatty acid amide hydrolase, urea inhibitor, golgi apparatus, endoplasmic reticulum, acyl- enzyme, transmembrane, phosphoprotein, faah, drug, membrane, hydrolase, 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: 120519.18

Authors

Mileni, M.,Kamtekar, S.,Stevens, R.C. (deposition date: 2009-02-11, release date: 2009-05-05, Last modification date: 2023-12-13)

Primary citation

Ahn, K.,Johnson, D.S.,Mileni, M.,Beidler, D.,Long, J.Z.,Mckinney, M.K.,Weerapana, E.,Sadagopan, N.,Liimatta, M.,Smith, S.E.,Lazerwith, S.,Stiff, C.,Kamtekar, S.,Bhattacharya, K.,Zhang, Y.,Swaney, S.,Vanbecelaere, K.,Stevens, R.C.,Cravatt, B.F.
Discovery and Characterization of a Highly Selective Faah Inhibitor that Reduces Inflammatory Pain.
Chem.Biol., 16:411-, 2009

PubMed Abstract: Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

PubMed: 19389627
DOI: 10.1016/J.CHEMBIOL.2009.02.013

Experimental method

X-RAY DIFFRACTION (2.8 Å)