Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Academic Article

abstract

• Resistance to isoniazid in Mycobacterium tuberculosis can be mediated by substitution of alanine for serine 94 in the InhA protein, the drug's primary target. InhA was shown to catalyze the beta-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-trans-enoyl-acyl carrier protein, an essential step in fatty acid elongation. Kinetic analyses suggested that isoniazid resistance is due to a decreased affinity of the mutant protein for NADH. The three-dimensional structures of wild-type and mutant InhA, refined to 2.2 and 2.7 angstroms, respectively, revealed that drug resistance is directly related to a perturbation in the hydrogen-bonding network that stabilizes NADH binding.

authors

• Sacchettini, James

published proceedings

• Science

altmetric score

• 6

author list (cited authors)

• Dessen, A., Qumard, A., Blanchard, J. S., Jacobs, W. R., & Sacchettini, J. C.

citation count

• 365

complete list of authors

• Dessen, A||Quémard, A||Blanchard, JS||Jacobs, WR||Sacchettini, JC

publication date

• March 1995

publisher

• American Association for the Advancement of Science (AAAS)  Publisher

published in

• Science  Journal

keywords

• Bacterial Proteins
• Binding Sites
• Computer Graphics
• Crystallization
• Crystallography, X-Ray
• Drug Resistance, Microbial
• Hydrogen Bonding
• Isoniazid
• Models, Molecular
• Mycobacterium Tuberculosis
• NAD
• Oxidation-Reduction
• Oxidoreductases
• Protein Conformation
• Protein Folding
• Protein Structure, Secondary

PubMed Central ID

• 7886450

Digital Object Identifier (DOI)

• 10.1126/science.7886450

start page

• 1638

end page

• 1641

volume

• 267

issue

• 5204