2VKZ

Structure of the cerulenin-inhibited fungal fatty acid synthase type I multienzyme complex

2VKZ の概要

• エントリーDOI: 10.2210/pdb2vkz/pdb
• 関連するPDBエントリー: 2UV8
• 分子名称: FATTY ACID SYNTHASE SUBUNIT ALPHA, FATTY ACID SYNTHASE SUBUNIT BETA, (2S, 3R)-3-HYDROXY-4-OXO-7,10-TRANS,TRANS-DODECADIENAMIDE, ... (4 entities in total)
• 機能のキーワード: transferase, phosphorylation, phosphopantetheine, fatty acid synthase, multifunctional enzyme, oxidoreductase, lipid synthesis, fas, nad, nadp, lyase, cerulenin, hydrolase, fatty acid biosynthesis
• 由来する生物種: SACCHAROMYCES CEREVISIAE (BAKER'S YEAST); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 1310419.27

構造登録者

Johansson, P.,Wiltschi, B.,Kumari, P.,Kessler, B.,Vonrhein, C.,Vonck, J.,Oesterhelt, D.,Grininger, M. (登録日: 2008-01-07, 公開日: 2008-08-12, 最終更新日: 2024-11-20)

主引用文献

Johansson, P.,Wiltschi, B.,Kumari, P.,Kessler, B.,Vonrhein, C.,Vonck, J.,Oesterhelt, D.,Grininger, M.
Inhibition of the Fungal Fatty Acid Synthase Type I Multienzyme Complex.
Proc.Natl.Acad.Sci.USA, 105:12803-, 2008

PubMed Abstract: Fatty acids are among the major building blocks of living cells, making lipid biosynthesis a potent target for compounds with antibiotic or antineoplastic properties. We present the crystal structure of the 2.6-MDa Saccharomyces cerevisiae fatty acid synthase (FAS) multienzyme in complex with the antibiotic cerulenin, representing, to our knowledge, the first structure of an inhibited fatty acid megasynthase. Cerulenin attacks the FAS ketoacyl synthase (KS) domain, forming a covalent bond to the active site cysteine C1305. The inhibitor binding causes two significant conformational changes of the enzyme. First, phenylalanine F1646, shielding the active site, flips and allows access to the nucleophilic cysteine. Second, methionine M1251, placed in the center of the acyl-binding tunnel, rotates and unlocks the inner part of the fatty acid binding cavity. The importance of the rotational movement of the gatekeeping M1251 side chain is reflected by the cerulenin resistance and the changed product spectrum reported for S. cerevisiae strains mutated in the adjacent glycine G1250. Platensimycin and thiolactomycin are two other potent inhibitors of KSs. However, in contrast to cerulenin, they show selectivity toward the prokaryotic FAS system. Because the flipped F1646 characterizes the catalytic state accessible for platensimycin and thiolactomycin binding, we superimposed structures of inhibited bacterial enzymes onto the S. cerevisiae FAS model. Although almost all side chains involved in inhibitor binding are conserved in the FAS multienzyme, a different conformation of the loop K1413-K1423 of the KS domain might explain the observed low antifungal properties of platensimycin and thiolactomycin.

PubMed: 18725634
DOI: 10.1073/PNAS.0805827105

実験手法

X-RAY DIFFRACTION (4 Å)