Lack of dynamics in the MabA active site kills the enzyme activity: practical consequences for drug-design studies.
The MabA protein from Mycobacterium tuberculosis is a validated drug target. Previous structural studies of this protein showed dynamic behaviour in the catalytic site and described motion between an open 'active' holo form (with NADP) and a closed 'inactive' apo form (without NADP). Here, a mutation (G139A) is reported that leads to complete protein inactivation and freezes the catalytic site into its closed form, even in the presence of the cofactor. This observation suggests a new way to develop anti-MabA drugs via protein stabilization of the 'inactive' form.
Poncet-Montange
Guillaume
G
CNRS UMR5048, Centre de Biochimie Structurale, F-34090 Montpellier, France.
Ducasse-Cabanot
Stephanie
S
Quemard
Annaick
A
Labesse
Gilles
G
Cohen-Gonsaud
Martin
M
D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D015195:Drug Design; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D017434:Protein Structure, Tertiary
D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase