Ligand-induced fit in mycobacterial MabA: the sequence-specific C-terminus locks the conformational change.
The protein MabA of Mycobacterium tuberculosis is a beta-ketoacyl reductase (KAR) and catalyses one of the four steps of the fatty acid elongation system FAS-II. The crystal structures of different KARs revealed a significant rearrangements of the active site between a "closed" inactive conformation and an "open" and active form in presence of the cofactor. MabA is a potential therapeutic target. However, only the structure of the "closed" form was obtained and rational drug design requires the structure of the active form. Here we described the sequences and structures analysis of the KARs to stabilize the "open form" in MabA. The crystal structure of a mutated MabA protein was then solved in both inactive and active form. The crystal structure of the wild-type MabA in the presence of NADP was also solved and showing a mixture of the two mutually exclusive conformations. This new structure of MabA is analyzed in view of its distinctive enzymatic and structural properties and those of related enzymes.
Cohen-Gonsaud
Martin
M
Centre de Biochimie Structurale INSERM U554, CNRS UMR5048, UM1, Montpellier cedex, France. m.cohen-gonsaud@bbk.ac.uk
Ducasse-Cabanot
Stéphanie
S
Quemard
Annaïk
A
Labesse
Gilles
G
D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D002586:Cesium / Q000737:chemistry; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004926:Escherichia coli / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013237:Stereoisomerism; D013379:Substrate Specificity
D008024:Ligands; D002586:Cesium; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase