Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex that Confer Multi-Nucleoside Drug Resistance [PublishAheadOfPrint]

HIV-1 reverse transcriptase (RT) is targeted by multiple drugs. RT mutations emerge that confer resistance to nucleoside RT inhibitors (NRTIs) in clinical use. Q151M, and four associated mutations A62V, V75I, F77L, and F116Y were detected in patients failing therapies to dideoxynucleosides (didanosine, ddI; zalcitabine, ddC) and/or zidovudine (AZT). The cluster of the five mutations is referred to as the Q151M complex (Q151Mc), and an RT or virus containing Q151Mc exhibits resistance to multiple NRTIs. To understand the structural basis for Q151M and Q151Mc resistance, we have systematically determined crystal structures of wild-type RT/dsDNA/dATP (I), wild-type RT/dsDNA/ddATP (II), Q151M RT/dsDNA/dATP (III), Q151Mc RT/dsDNA/dATP (IV), and Q151Mc RT/dsDNA/ddATP (V) ternary complexes. The structures revealed that the deoxyribose rings of dATP and ddATP have 3' -endo and 3' -exo conformations, respectively. The single mutation Q151M introduces conformational perturbation at the dNTP-binding pocket, and the mutated pocket may exist in multiple conformations. The compensatory set of mutations in Q151Mc, particularly F116Y, restricts the side-chain flexibility of M151 and helps restore the DNA polymerization efficiency of the enzyme. The altered dNTP-binding pocket in Q151Mc RT has the Q151-R72 hydrogen bond removed, and has a switched conformation for the key conserved residue R72 compared to that in wtRT. Based on a modeled structure of hepatitis B (HBV) polymerase, the residues R72, Y116, M151, and M184 in Q151Mc HIV-1 RT are conserved in wild-type HBV polymerase as residues R41, Y89, M171, and M204, respectively; functionally, both Q151Mc HIV-1 and wild-type HBV are resistant to dideoxynucleoside analogs.

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