The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with β-branched amino acids
Open accessAbstract
An important component of triple-drug anti-AIDS therapy is 2′,3′-dideoxy-3′-thiacytidine (3TC, lamivudine). Single mutations at residue 184 of the reverse transcriptase (RT) in HIV cause high-level resistance to 3TC and contribute to the failure of anti-AIDS combination therapy. We have determined crystal structures of the 3TC-resistant mutant HIV-1 RT (M184I) in both the presence and absence of a DNA/DNA template-primer. In the absence of a DNA substrate, the wild-type and mutant structures are very similar. However, comparison of crystal structures of M184I mutant and wild-type HIV-1 RT with and without DNA reveals repositioning of the template-primer in the M184I/DNA binary complex and other smaller changes in residues in the dNTP-binding site. On the basis of these structural results, we developed a model that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP. In this model, steric hindrance is expected for NRTIs with β- or l - ring configurations, as with the enantiomer of 3TC that is used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and the side chain of β-branched amino acids (Val, Ile, Thr) at position 184 perturbs inhibitor binding, leading to a reduction in incorporation of the analog. The model can also explain the 3TC resistance of analogous hepatitis B polymerase mutants. Repositioning of the template-primer as observed in the binary complex (M184I/DNA) may also occur in the catalytic ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by interfering with the formation of a catalytically competent closed complex.
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Self-citationA Preliminary Trial of Lamivudine for Chronic Hepatitis B Infection
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Resistance to ddI and Sensitivity to AZT Induced by a Mutation in HIV-1 Reverse Transcriptase
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Cited by
Menéndez-Arias, L., Sebastián-Martín, A., & Álvarez, M. (2017) · Virus Research · doi:10.1016/j.virusres.2016.12.019 · Cited by 123
Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs)
Sluis-Cremer, N., Arion, D., & Parniak*, M. A. (2000) · Cellular and Molecular Life Sciences · doi:10.1007/pl00000626 · Cited by 117
Avoiding drug resistance in HIV reverse transcriptase
Cilento, M. E., Kirby, K. A., & Sarafianos, S. G. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00967 · Cited by 106
Self-citationKankanala, J., Kirby, K. A., Liu, F., Miller, L., Nagy, E., Wilson, D. J., Parniak, M. A., Sarafianos, S. G., & Wang, Z. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00465 · Cited by 66
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Metadata
- Authors
- Sarafianos, S. G., Das, K., Clark, A. D., Ding, J., Boyer, P. L., Hughes, S. H., & Arnold, E.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 1999-08-31
- Volume
- 96
- Issue
- 18
- Pages
- 10027-10032
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2119855246
- Cited by
- 309
- References
- 44
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- green
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