A structural frame for understanding the role of thymidine analogue resistance mutations in resistance to zidovudine and other nucleoside analogues.
The acquisition of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) can be mediated by amino acid changes at the dNTP binding site that affect the catalytic efficiency of nucleotide analogue incorporation, or by mutations that, in the presence of a pyrophosphate donor, facilitate excision of 3'-terminal chain-terminating inhibitors from blocked primers. These mutations, known as thymidine analogue resistance mutations (TAMs) are M41L, D67N, K70R, L210W, T215F/Y and K219E/Q. Recently published crystal structures of wild-type and TAM-containing HIV-1 reverse transcriptases bound to double-stranded DNA and the excision product, azidothymidine adenosine dinucleoside tetraphosphate have shed light into the molecular mechanism of excision.
Centro de Biología Molecular 'Severo Ochoa' (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), c/ Nicolás Cabrera 1, Campus de Cantoblanco, Madrid, Spain. lmenendez@cbm.uam.es
Luis
L
Menéndez-Arias
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D020134:Catalytic Domain; D004247:DNA / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology*
D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D004247:DNA; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D013936:Thymidine