2PX6

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

2PX6 の概要

• エントリーDOI: 10.2210/pdb2px6/pdb
• 分子名称: 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)
• 機能のキーワード: thioesaterse domain, orlistat, fatty acid synthase, drug complex, tetrahydrolipstatin, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P49327
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70644.16

構造登録者

Pemble IV, C.W.,Johnson, L.C.,Kridel, S.J.,Lowther, W.T. (登録日: 2007-05-14, 公開日: 2007-07-10, 最終更新日: 2024-10-30)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)