2PX6

Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat

Summary for 2PX6

• Entry DOI: 10.2210/pdb2px6/pdb
• Descriptor: Thioesterase domain, (2S,3S,5S)-5-[(N-FORMYL-L-LEUCYL)OXY]-2-HEXYL-3-HYDROXYHEXADECANOIC ACID, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (4 entities in total)
• Functional Keywords: thioesaterse domain, orlistat, fatty acid synthase, drug complex, tetrahydrolipstatin, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P49327
• Total number of polymer chains: 2
• Total formula weight: 70644.16

Authors

Pemble IV, C.W.,Johnson, L.C.,Kridel, S.J.,Lowther, W.T. (deposition date: 2007-05-14, release date: 2007-07-10, Last modification date: 2024-10-30)

Primary citation

Pemble, C.W.,Johnson, L.C.,Kridel, S.J.,Lowther, W.T.
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat.
Nat.Struct.Mol.Biol., 14:704-709, 2007

PubMed Abstract: Human fatty acid synthase (FAS) is uniquely expressed at high levels in many tumor types. Pharmacological inhibition of FAS therefore represents an important therapeutic opportunity. The drug Orlistat, which has been approved by the US Food and Drug Administration, inhibits FAS, induces tumor cell-specific apoptosis and inhibits the growth of prostate tumor xenografts. We determined the 2.3-A-resolution crystal structure of the thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in the active sites of two thioesterase molecules as a stable acyl-enzyme intermediate and as the hydrolyzed product. The details of these interactions reveal the molecular basis for inhibition and suggest a mechanism for acyl-chain length discrimination during the FAS catalytic cycle. Our findings provide a foundation for the development of new cancer drugs that target FAS.

PubMed: 17618296
DOI: 10.1038/nsmb1265

Experimental method

X-RAY DIFFRACTION (2.3 Å)