HIV reverse transcriptase: Structural interpretation of drug resistant genetic variants from India
Journal Title: Bioinformation - Year 2009, Vol 4, Issue 1
Abstract
The reverse transcriptase (RT) enzyme is the prime target of nucleoside/ nucleotide (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors. Here we investigate the structural basis of effects of drug-resistance mutations in clade C RT using three-dimensional structural modeling. Apropos the expectation was for unique mechanisms in clade C based on interactions with amino acids of p66 subunit in RT molecule. 3-D structures of RT with mutations found in sequences from 2 treatment naïve, 8 failed and one reference clade C have been modeled and analyzed. Models were generated by computational mutation of available crystal structures of drug bound homologous RT. Energy minimization of the models and the structural analyses were carried out using standard methods. Mutations at positions 75,101,118,190,230,238 and 318 known to confer drug resistance were investigated. Different mutations produced different effects such as alteration of geometry of the drugbinding pocket, structural changes at the site of entry of the drug (into the active site), repositioning the template bases or by discriminating the inhibitors from their natural substrates. For the mutations analyzed, NRTI resistance was mediated mainly by the ability to discriminate between inhibitors and natural substrate, whereas, NNRTI resistance affected either the drug entry or the geometry of the active site. Our analysis suggests that different mutations result in different structural effects affecting the ability of a given drug to bind to the RT. Our studies will help in the development of newer drugs taking into account the presence of these mutations and the structural basis of drug resistance.
Authors and Affiliations
Abraham J. Kandathil , Agnel P. Joseph , R. Kannangai , N. Srinivasan , Oriapadicakal C. Abraham , Susanne A. Pulimood , G. Sridharan ,
Keywords
Related Articles
- EP ID EP86367
- DOI 10.6026/97320630004036
- Views 174
- Downloads 0
Intergenics: A tool for extraction of intergenicregions.
For the past one decade, there has been considerable explosion of interest in searching novel regulatory elements in the intergenic region between the protein coding regions. The microbial genomes are the most exploited...
Robust consensus clustering for identification of expressed genes linked to malignancy of human colorectal carcinoma.
Previous studies have been conducted in gene expression profiling to identify groups of genes that characterize the colorectal carcinoma disease. Despite the success of previous attempts to identify groups of genes in th...
Analysis of casein alpha S1 & S2 proteins from different mammalian species.
Nowadays, the quality of any food used for human consumption is, to a considerable extent, considered by its possible contribution to the maintenance or improvement of the consumer's health. In developed countries there...
A prognostic model for the combined analysis of gene expression profiling in hepatocellular carcinoma.
Microarray techniques using cDNA array and comparative genomic hybridization (CGH) have been developed for several discovery applications. They are frequently applied for the prediction and diagnosis of cancer in recent...
Modeling of pyruvate decarboxylases from ethanol producing bacteria.
Pyruvate decarboxylase (PDC) is a key enzyme in homoethanol fermentation process, which decarboxylates 2-keto acid pyruvate into acetaldehyde and carbon dioxide. PDC enzymes from potential ethanol-producing bacteria such...