2vkz

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

spinqualitylabelsall models 2vkz, resolution 4.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2vkz is a 6 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CER, FMN Related: 2uv8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Warning: this is a large structure, and loading might take a long time or not happen at all. Function [FAS2_YEAST] Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. The alpha subunit contains domains for: acyl carrier protein, 3-oxoacyl-[acyl-carrier-protein] reductase, and 3-oxoacyl-[acyl-carrier-protein] synthase. This subunit coordinates the binding of the six beta subunits to the enzyme complex.[HAMAP-Rule:MF_00101] [FAS1_YEAST] Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. The beta subunit contains domains for: [acyl-carrier-protein] acetyltransferase and malonyltransferase, S-acyl fatty acid synthase thioesterase, enoyl-[acyl-carrier-protein] reductase, and 3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Inhibition of the fungal fatty acid synthase type I multienzyme complex.,Johansson P, Wiltschi B, Kumari P, Kessler B, Vonrhein C, Vonck J, Oesterhelt D, Grininger M Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12803-8. Epub 2008 Aug 25. PMID:18725634 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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