TY - JOUR
T1 - Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis
AU - Dessen, Andréa
AU - Quémard, Annaïk
AU - Blanchard, John S.
AU - Jacobs, William R.
AU - Sacchettini, James C.
PY - 1995
Y1 - 1995
N2 - 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 β-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-transenoyl-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.
AB - 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 β-nicotinamide adenine dinucleotide (NADH)-specific reduction of 2-transenoyl-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.
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U2 - 10.1126/science.7886450
DO - 10.1126/science.7886450
M3 - Article
C2 - 7886450
AN - SCOPUS:0028988237
SN - 0036-8075
VL - 267
SP - 1638
EP - 1641
JO - Science
JF - Science
IS - 5204
ER -
