Inhibition of Mycobacterium tuberculosis InhA by 3-nitropropanoic acid.
Proteins
; 90(3): 898-904, 2022 03.
Article
en En
| MEDLINE
| ID: mdl-34677871
ABSTRACT
3-Nitropropanoic acid (3NP), a bioactive fungal natural product, was previously demonstrated to inhibit growth of Mycobacterium tuberculosis. Here we demonstrate that 3NP inhibits the 2-trans-enoyl-acyl carrier protein reductase (InhA) from Mycobacterium tuberculosis with an IC50 value of 71 µM, and present the crystal structure of the ternary InhA-NAD+ -3NP complex. The complex contains the InhA substrate-binding loop in an ordered, open conformation with Tyr158, a catalytically important residue whose orientation defines different InhA substrate/inhibitor complex conformations, in the "out" position. 3NP occupies a hydrophobic binding site adjacent to the NAD+ cofactor and close to that utilized by the diphenyl ether triclosan, but binds predominantly via electrostatic and water-mediated hydrogen-bonding interactions with the protein backbone and NAD+ cofactor. The identified mode of 3NP binding provides opportunities to improve inhibitory activity toward InhA.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oxidorreductasas
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Propionatos
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Proteínas Bacterianas
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Mycobacterium tuberculosis
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Nitrocompuestos
Idioma:
En
Año:
2022
Tipo del documento:
Article