Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance

Hung, Magdeleine; Tokarsky, E. John; Lagpacan, Leanna; Zhang, Lijun; Suo, Zucai; Lansdon, Eric B.

doi:10.1038/s42003-019-0706-x

Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance

Journal Article · Thu Dec 12 23:00:00 EST 2019 · Communications Biology

DOI:https://doi.org/10.1038/s42003-019-0706-x· OSTI ID:1624535

Hung, Magdeleine ^[1]; Tokarsky, E. John ^[2]; Lagpacan, Leanna ^[3]; Zhang, Lijun ^[3]; Suo, Zucai ^[4]; ^[3]

Gilead Sciences, Inc., Foster City, CA (United States); DOE/OSTI
The Ohio State Univ., Columbus, OH (United States). The Ohio State Biophysics Program
Gilead Sciences, Inc., Foster City, CA (United States)
The Ohio State Univ., Columbus, OH (United States). The Ohio State Biophysics Program; Florida State Univ., College of Medicine, Tallahassee, FL (United States). Dept. of Biomedical Sciences

Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (-)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (-)-FTC-TP and (-)-3TC-TP and drug resistance by M184V. (-)-FTC-TP and (-)-3TC-TP have higher binding affinities (1/K_{d200-fold) K_d for the L-nucleotides and moderately higher (>9-fold) K_d for the D-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (-)-FTC-TP and shifts its triphosphate into a non-productive conformation.}

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624535

Journal Information:: Communications Biology, Journal Name: Communications Biology Journal Issue: 1 Vol. 2; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

References (43)

Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. Back, N. K.; Nijhuis, M.; Keulen, W. The EMBO Journal, Vol. 15, Issue 15 https://doi.org/10.1002/j.1460-2075.1996.tb00777.x	journal	August 1996
The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase 1 1Edited by A. R. Fersht Gao, Hong-Qiang; Boyer, Paul L.; Sarafianos, Stefan G. Journal of Molecular Biology, Vol. 300, Issue 2 https://doi.org/10.1006/jmbi.2000.3823	journal	July 2000
Telbivudine in the treatment of chronic hepatitis B Nash, Kathryn Advances in Therapy, Vol. 26, Issue 2 https://doi.org/10.1007/s12325-009-0004-y	journal	February 2009
Nucleotide substitution patterns can predict the requirements for drug-resistance of HIV-1 proteins Keulen, Wilco; Boucher, Charles; Berkhout, Ben Antiviral Research, Vol. 31, Issue 1-2 https://doi.org/10.1016/0166-3542(96)00944-8	journal	June 1996
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: A two-year study Gish, Robert G.; Trinh, Huy; Leung, Nancy Journal of Hepatology, Vol. 43, Issue 1 https://doi.org/10.1016/j.jhep.2005.02.017	journal	July 2005
Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex Lansdon, Eric B.; Samuel, Dharmaraj; Lagpacan, Leanna Journal of Molecular Biology, Vol. 397, Issue 4 https://doi.org/10.1016/j.jmb.2010.02.019	journal	April 2010
Single-Step Kinetics of HIV-1 Reverse Transcriptase Mutants Responsible for Virus Resistance to Nucleoside Inhibitors Zidovudine and 3-TC ^† Krebs, Ruth; Immendörfer, Ulrike; Thrall, Sara H. Biochemistry, Vol. 36, Issue 33 https://doi.org/10.1021/bi970512z	journal	August 1997
Mechanistic Studies Examining the Efficiency and Fidelity of DNA Synthesis by the 3TC-Resistant Mutant (184V) of HIV-1 Reverse Transcriptase ^† Feng, Joy Y.; Anderson, Karen S. Biochemistry, Vol. 38, Issue 29 https://doi.org/10.1021/bi990709m	journal	July 1999
Presteady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogues Catalyzed by Noncanonical Human DNA Polymerases Brown, Jessica A.; Pack, Lindsey R.; Fowler, Jason D. Chemical Research in Toxicology, Vol. 25, Issue 1 https://doi.org/10.1021/tx200458s	journal	December 2011
Structural basis of HIV-1 resistance to AZT by excision Tu, Xiongying; Das, Kalyan; Han, Qianwei Nature Structural & Molecular Biology, Vol. 17, Issue 10 https://doi.org/10.1038/nsmb.1908	journal	September 2010
Structures of HIV-1 RT–DNA complexes before and after incorporation of the anti-AIDS drug tenofovir Tuske, Steve; Sarafianos, Stefan G.; Clark, Arthur D. Nature Structural & Molecular Biology, Vol. 11, Issue 5 https://doi.org/10.1038/nsmb760	journal	April 2004
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Structural basis for the binding and incorporation of nucleotide analogs with L-stereochemistry by human DNA polymerase Vyas, R.; Zahurancik, W. J.; Suo, Z. Proceedings of the National Academy of Sciences, Vol. 111, Issue 30 https://doi.org/10.1073/pnas.1401286111	journal	July 2014
Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ Sohl, Christal D.; Szymanski, Michal R.; Mislak, Andrea C. Proceedings of the National Academy of Sciences, Vol. 112, Issue 28 https://doi.org/10.1073/pnas.1421733112	journal	June 2015
Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Tisdale, M.; Kemp, S. D.; Parry, N. R. Proceedings of the National Academy of Sciences, Vol. 90, Issue 12 https://doi.org/10.1073/pnas.90.12.5653	journal	June 1993
Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta -branched amino acids Sarafianos, S. G.; Das, K.; Clark, A. D. Proceedings of the National Academy of Sciences, Vol. 96, Issue 18 https://doi.org/10.1073/pnas.96.18.10027	journal	August 1999
Human Immunodeficiency Virus Type-1 Reverse Transcriptase: CONTRIBUTION OF MET-184 TO BINDING OF NUCLEOSIDE 5′-TRIPHOSPHATE Wilson, Jeanne E.; Aulabaugh, Ann; Caligan, Brent Journal of Biological Chemistry, Vol. 271, Issue 23 https://doi.org/10.1074/jbc.271.23.13656	journal	June 1996
Structural Basis for the Role of the K65R Mutation in HIV-1 Reverse Transcriptase Polymerization, Excision Antagonism, and Tenofovir Resistance Das, Kalyan; Bandwar, Rajiv P.; White, Kirsten L. Journal of Biological Chemistry, Vol. 284, Issue 50 https://doi.org/10.1074/jbc.M109.022525	journal	October 2009
Trapping HIV-1 Reverse Transcriptase Before and After Translocation on DNA Sarafianos, Stefan G.; Clark, Arthur D.; Tuske, Steve Journal of Biological Chemistry, Vol. 278, Issue 18 https://doi.org/10.1074/jbc.M212911200	journal	January 2003
Human Immunodeficiency Virus Type 1 Expressing the Lamivudine‐Associated M184V Mutation in Reverse Transcriptase Shows Increased Susceptibility to Adefovir and Decreased Replication Capability In Vitro Miller, Michael D.; Anton, Kristin E.; Mulato, Andrew S. The Journal of Infectious Diseases, Vol. 179, Issue 1 https://doi.org/10.1086/314560	journal	January 1999
Prospective Randomized Trial of Emtricitabine versus Lamivudine Short‐Term Monotherapy in Human Immunodeficiency Virus–Infected Patients Rousseau, Franck S.; Wakeford, Charles; Mommeja‐Marin, Herve The Journal of Infectious Diseases, Vol. 188, Issue 11 https://doi.org/10.1086/379667	journal	December 2003
Increased polymerase fidelity of the 3TC-resistant variants of HIV-1 reverse transcriptase Oude Essink, B. Nucleic Acids Research, Vol. 25, Issue 16 https://doi.org/10.1093/nar/25.16.3212	journal	August 1997
The processivity of DNA synthesis exhibited by drug-resistant variants of human immunodeficiency virus type-1 reverse transcriptase Avidan, O.; Hizi, A. Nucleic Acids Research, Vol. 26, Issue 7 https://doi.org/10.1093/nar/26.7.1713	journal	April 1998
Human immunodeficiency virus reverse transcriptase and protease sequence database Rhee, S. -Y. Nucleic Acids Research, Vol. 31, Issue 1 https://doi.org/10.1093/nar/gkg100	journal	January 2003
Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase Gaur, Vineet; Vyas, Rajan; Fowler, Jason D. Nucleic Acids Research, Vol. 42, Issue 15 https://doi.org/10.1093/nar/gku709	journal	August 2014
Structural basis for the D-stereoselectivity of human DNA polymerase β Vyas, Rajan; Reed, Andrew J.; Raper, Austin T. Nucleic Acids Research, Vol. 45, Issue 10 https://doi.org/10.1093/nar/gkx252	journal	April 2017
Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP Feng, Joy Y.; Shi, Junxing; Schinazi, Raymond F. The FASEB Journal, Vol. 13, Issue 12 https://doi.org/10.1096/fasebj.13.12.1511	journal	September 1999
A combination of decreased NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT White, Kirsten L.; Margot, Nicolas A.; Ly, John K. AIDS, Vol. 19, Issue 16 https://doi.org/10.1097/01.aids.0000189851.21441.f1	journal	January 2005
A neutron-diffraction study of the low-cycle fatigue behaviour of an austenitic stainless steel 316 Dubreuil, Adelaide; Zhang, Shu Yan; Eve, Sophie Acta Crystallographica Section A Foundations of Crystallography, Vol. 66, Issue a1 https://doi.org/10.1107/S010876731009728X	journal	August 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance Huang, H. Science, Vol. 282, Issue 5394 https://doi.org/10.1126/science.282.5394.1669	journal	November 1998
Pre-Steady-State Kinetic Analysis of the Incorporation of Anti-HIV Nucleotide Analogs Catalyzed by Human X- and Y-Family DNA Polymerases Brown, Jessica A.; Pack, Lindsey R.; Fowler, Jason D. Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 1 https://doi.org/10.1128/AAC.01229-10	journal	November 2010
Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Schinazi, R. F.; McMillan, A.; Cannon, D. Antimicrobial Agents and Chemotherapy, Vol. 36, Issue 11 https://doi.org/10.1128/AAC.36.11.2423	journal	November 1992
Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Schinazi, R. F.; Lloyd, R. M.; Nguyen, M. H. Antimicrobial Agents and Chemotherapy, Vol. 37, Issue 4 https://doi.org/10.1128/AAC.37.4.875	journal	April 1993
Analysis of mutations at position 184 in reverse transcriptase of human immunodeficiency virus type 1 Boyer, P. L.; Hughes, S. H. Antimicrobial Agents and Chemotherapy, Vol. 39, Issue 7 https://doi.org/10.1128/AAC.39.7.1624	journal	July 1995
Molecular Impact of the M184V Mutation in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Diallo, Karidia; Götte, Matthias; Wainberg, M. A. Antimicrobial Agents and Chemotherapy, Vol. 47, Issue 11 https://doi.org/10.1128/AAC.47.11.3377-3383.2003	journal	November 2003
Tenofovir Resistance and Resensitization Wolf, Katharina; Walter, Hauke; Beerenwinkel, Niko Antimicrobial Agents and Chemotherapy, Vol. 47, Issue 11 https://doi.org/10.1128/AAC.47.11.3478-3484.2003	journal	November 2003
Safety, Pharmacokinetics, and Efficacy of (+/−)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine with Efavirenz and Stavudine in Antiretroviral-Naïve Human Immunodeficiency Virus-Infected Patients Herzmann, C.; Arastèh, K.; Murphy, R. L. Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 7 https://doi.org/10.1128/AAC.49.7.2828-2833.2005	journal	July 2005
In Vitro Antiretroviral Activity and In Vitro Toxicity Profile of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor for Treatment of Human Immunodeficiency Virus Infection Gu, Z.; Allard, B.; de Muys, J. M. Antimicrobial Agents and Chemotherapy, Vol. 50, Issue 2 https://doi.org/10.1128/AAC.50.2.625-631.2006	journal	February 2006
Initial appearance of the 184Ile variant in lamivudine-treated patients is caused by the mutational bias of human immunodeficiency virus type 1 reverse transcriptase. Keulen, W.; Back, N. K.; van Wijk, A. Journal of virology, Vol. 71, Issue 4 https://doi.org/10.1128/JVI.71.4.3346-3350.1997	journal	January 1997
Evolution of Lamivudine Resistance in Human Immunodeficiency Virus Type 1-Infected Individuals: the Relative Roles of Drift and Selection Frost, Simon D. W.; Nijhuis, Monique; Schuurman, Rob Journal of Virology, Vol. 74, Issue 14 https://doi.org/10.1128/JVI.74.14.6262-6268.2000	journal	July 2000
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

Similar Records

Structural and kinetic insights into binding and incorporation of L-nucleotide analogs by a Y-family DNA polymerase

Journal Article · Thu Aug 07 00:00:00 EDT 2014 · Nucleic Acids Research · OSTI ID:1625540

Structure of the HIV-1 reverse transcriptase Q151M mutant: insights into the inhibitor resistance of HIV-1 reverse transcriptase and the structure of the nucleotide-binding pocket of Hepatitis B virus polymerase

Journal Article · Fri Oct 23 00:00:00 EDT 2015 · Acta Crystallographica. Section F, Structural Biology Communications · OSTI ID:22515175

Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance

Journal Article · Wed Oct 21 00:00:00 EDT 2020 · Molecules · OSTI ID:1691541

Related Subjects

Life Sciences & Biomedicine - Other Topics
Science & Technology - Other Topics

Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance

Citation Formats

References (43)

Similar Records

Related Subjects