Crystal Structure and Function of the Isoniazid Target of Mycobacterium tuberculosis
| Autor: | William R. Jacobs, Andréa Dessen, John S. Blanchard, James C. Sacchettini, Annaik Quemard |
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| Rok vydání: | 1995 |
| Předmět: |
Models
Molecular Protein Folding Protein Conformation NADH binding Enoyl-acyl carrier protein reductase Crystallography X-Ray Protein Structure Secondary Mycobacterium tuberculosis Bacterial Proteins Mutant protein Computer Graphics Isoniazid medicine Antibacterial agent Binding Sites Multidisciplinary biology INHA Drug Resistance Microbial Hydrogen Bonding NAD biology.organism_classification Biochemistry Fatty acid elongation Crystallization Oxidoreductases Oxidation-Reduction medicine.drug |
| Zdroj: | Science. 267:1638-1641 |
| ISSN: | 1095-9203 0036-8075 |
| DOI: | 10.1126/science.7886450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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