Refined structures of beta-ketoacyl-acyl carrier protein synthase III.
beta-Ketoacyl-acyl carrier protein synthase III (FabH) is a condensing enzyme that plays central roles in fatty acid biosynthesis. Three-dimensional structures of E. coli FabH in the presence and absence of ligands have been refined to 1.46 A resolution. The structures of improved accuracy revealed detailed interactions involved in ligand binding. These structures also provided new insights into the FabH mechanism, e.g. the possible role of a water or hydroxyl anion in Cys112 deprotonation. A structure of the apo enzyme uncovered large conformational changes in the active site, exemplified by the disordering of four essential loops (84-86, 146-152, 185-217 and 305-307) and the movement of catalytic residues (Cys112 and His244). The disordering of the loops leads to greater than 50 % reduction in the FabH dimer interface, suggesting a dynamic nature for an unusually large portion of the dimer interface. The existence of a large solvent-accessible channel in the dimer interface as well as two cis-peptides (cis-Pro88 and cis-Phe308) in two of the disordered loops may explain the observed structural instabilities.
Department of Structural Biology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA. xiayang_qui-1@sbphrd.com
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Qiu
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Janson
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Lonsdale
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Konstantinidis
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000737:chemistry* / Q000378:metabolism; D000107:Acetylation; D000595:Amino Acid Sequence; D003065:Coenzyme A / Q000737:chemistry; D003460:Crystallization; D003653:Decarboxylation; D004926:Escherichia coli / Q000737:chemistry / Q000201:enzymology; D008316:Malonyl Coenzyme A / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D008316:Malonyl Coenzyme A; C077402:3-ketoacyl-acyl carrier protein synthase III; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; D003065:Coenzyme A