Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine
Abstract
ABSTRACT The retrovirus HIV‐1 has been a major health issue since its discovery in the early 80s. In 2017, over 37 million people were infected with HIV‐1, of which 1.8 million were new infections that year. Currently, the most successful treatment regimen is the highly active antiretroviral therapy (HAART), which consists of a combination of three to four of the current 26 FDA‐approved HIV‐1 drugs. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. One class of RT inhibitors is nucleoside reverse transcriptase inhibitors (NRTIs), a crucial component of the HAART. Once incorporated into DNA, NRTIs function as a chain terminator to stop viral DNA replication. Unfortunately, treatment with NRTIs is sometimes linked to toxicity caused by off‐target side effects. NRTIs may also target the replicative human mitochondrial DNA polymerase (Pol γ), causing long‐term severe drug toxicity. The goal of this work is to understand the discrimination mechanism of different NRTI analogues by RT. Crystal structures and kinetic experiments are essential for the rational design of new molecules that are able to bind selectively to RT and not Pol γ. Structural comparison of NRTI‐binding modes with both RT and Pol γ enzymes highlightsmore »
- Authors:
-
- Department of Pharmacology Yale University School of Medicine New Haven Connecticut
- Laboratory of Biochemical Pharmacology, Department of Pediatrics, Center for AIDS Research Emory University School of Medicine Atlanta Georgia
- Department of Pharmacology and Toxicology University of Texas Medical Branch Galveston Texas, Sealy Center for Structural Biology University of Texas Medical Branch Galveston Texas
- Department of Pharmacology Yale University School of Medicine New Haven Connecticut, Department of Molecular Biophysics and Biochemistry Yale University School of Medicine New Haven Connecticut
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1547084
- Resource Type:
- Publisher's Accepted Manuscript
- Journal Name:
- Protein Science
- Additional Journal Information:
- Journal Name: Protein Science Journal Volume: 28 Journal Issue: 9; Journal ID: ISSN 0961-8368
- Publisher:
- Wiley Blackwell (John Wiley & Sons)
- Country of Publication:
- United Kingdom
- Language:
- English
Citation Formats
Bertoletti, Nicole, Chan, Albert H., Schinazi, Raymond F., Yin, Y. Whitney, and Anderson, Karen S.. Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine. United Kingdom: N. p., 2019.
Web. doi:10.1002/pro.3681.
Bertoletti, Nicole, Chan, Albert H., Schinazi, Raymond F., Yin, Y. Whitney, & Anderson, Karen S.. Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine. United Kingdom. https://doi.org/10.1002/pro.3681
Bertoletti, Nicole, Chan, Albert H., Schinazi, Raymond F., Yin, Y. Whitney, and Anderson, Karen S.. Tue .
"Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine". United Kingdom. https://doi.org/10.1002/pro.3681.
@article{osti_1547084,
title = {Structural insights into the recognition of nucleoside reverse transcriptase inhibitors by HIV‐1 reverse transcriptase: First crystal structures with reverse transcriptase and the active triphosphate forms of lamivudine and emtricitabine},
author = {Bertoletti, Nicole and Chan, Albert H. and Schinazi, Raymond F. and Yin, Y. Whitney and Anderson, Karen S.},
abstractNote = {ABSTRACT The retrovirus HIV‐1 has been a major health issue since its discovery in the early 80s. In 2017, over 37 million people were infected with HIV‐1, of which 1.8 million were new infections that year. Currently, the most successful treatment regimen is the highly active antiretroviral therapy (HAART), which consists of a combination of three to four of the current 26 FDA‐approved HIV‐1 drugs. Half of these drugs target the reverse transcriptase (RT) enzyme that is essential for viral replication. One class of RT inhibitors is nucleoside reverse transcriptase inhibitors (NRTIs), a crucial component of the HAART. Once incorporated into DNA, NRTIs function as a chain terminator to stop viral DNA replication. Unfortunately, treatment with NRTIs is sometimes linked to toxicity caused by off‐target side effects. NRTIs may also target the replicative human mitochondrial DNA polymerase (Pol γ), causing long‐term severe drug toxicity. The goal of this work is to understand the discrimination mechanism of different NRTI analogues by RT. Crystal structures and kinetic experiments are essential for the rational design of new molecules that are able to bind selectively to RT and not Pol γ. Structural comparison of NRTI‐binding modes with both RT and Pol γ enzymes highlights key amino acids that are responsible for the difference in affinity of these drugs to their targets. Therefore, the long‐term goal of this research is to develop safer, next generation therapeutics that can overcome off‐target toxicity.},
doi = {10.1002/pro.3681},
journal = {Protein Science},
number = 9,
volume = 28,
place = {United Kingdom},
year = {2019},
month = {8}
}
https://doi.org/10.1002/pro.3681
Web of Science
Works referenced in this record:
Insights into the Molecular Mechanism of Mitochondrial Toxicity by AIDS Drugs
journal, April 2001
- Feng, Joy Y.; Johnson, Allison A.; Johnson, Kenneth A.
- Journal of Biological Chemistry, Vol. 276, Issue 26
Relationship between Antiviral Activity and Host Toxicity: Comparison of the Incorporation Efficiencies of 2',3'-Dideoxy-5-Fluoro-3'-Thiacytidine-Triphosphate Analogs by Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Human Mitochondrial DNA Polymerase
journal, March 2004
- Feng, J. Y.; Murakami, E.; Zorca, S. M.
- Antimicrobial Agents and Chemotherapy, Vol. 48, Issue 4
Trapping HIV-1 Reverse Transcriptase Before and After Translocation on DNA
journal, January 2003
- Sarafianos, Stefan G.; Clark, Arthur D.; Tuske, Steve
- Journal of Biological Chemistry, Vol. 278, Issue 18
Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ
journal, June 2015
- Sohl, Christal D.; Szymanski, Michal R.; Mislak, Andrea C.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 28
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Structure of HIV-1 reverse transcriptase/d4TTP complex: Novel DNA cross-linking site and pH-dependent conformational changes: RT/d4TTP structure with novel DNA cross-link
journal, December 2018
- Martinez, Sergio E.; Bauman, Joseph D.; Das, Kalyan
- Protein Science, Vol. 28, Issue 3
Structural basis for the binding and incorporation of nucleotide analogs with L-stereochemistry by human DNA polymerase
journal, July 2014
- Vyas, R.; Zahurancik, W. J.; Suo, Z.
- Proceedings of the National Academy of Sciences, Vol. 111, Issue 30
Collaboration gets the most out of software
journal, September 2013
- Morin, Andrew; Eisenbraun, Ben; Key, Jason
- eLife, Vol. 2
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Interactions of enantiomers of 2′,3′-didehydro-2′,3′-dideoxy-fluorocytidine with wild type and M184V mutant HIV-1 reverse transcriptase
journal, December 2002
- Ray, A.; Murakami, E.; Peterson, C.
- Antiviral Research, Vol. 56, Issue 3
Mechanism and fidelity of HIV reverse transcriptase.
journal, December 1992
- Kati, W. M.; Johnson, K. A.; Jerva, L. F.
- Journal of Biological Chemistry, Vol. 267, Issue 36
Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP
journal, September 1999
- Feng, Joy Y.; Shi, Junxing; Schinazi, Raymond F.
- The FASEB Journal, Vol. 13, Issue 12
Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV
journal, July 2019
- Kudalkar, Shalley N.; Ullah, Irfan; Bertoletti, Nicole
- Antiviral Research, Vol. 167
Nonnucleoside Inhibitor Binding Affects the Interactions of the Fingers Subdomain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase with DNA
journal, March 2004
- Peletskaya, E. N.; Kogon, A. A.; Tuske, S.
- Journal of Virology, Vol. 78, Issue 7
Mechanistic Studies Comparing the Incorporation of (+) and (−) Isomers of 3TCTP by HIV-1 Reverse Transcriptase †
journal, January 1999
- Feng, Joy Y.; Anderson, Karen S.
- Biochemistry, Vol. 38, Issue 1
Solvent content of protein crystals
journal, April 1968
- Matthews, B. W.
- Journal of Molecular Biology, Vol. 33, Issue 2
Probing the Mechanistic Consequences of 5-Fluorine Substitution on Cytidine Nucleotide Analogue Incorporation by HIV-1 Reverse Transcriptase
journal, June 2003
- Ray, Adrian S.; Schinazi, Raymond F.; Murakami, Eisuke
- Antiviral Chemistry and Chemotherapy, Vol. 14, Issue 3
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
PROCHECK: a program to check the stereochemical quality of protein structures
journal, April 1993
- Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.
- Journal of Applied Crystallography, Vol. 26, Issue 2
Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
journal, November 1992
- Schinazi, R. F.; McMillan, A.; Cannon, D.
- Antimicrobial Agents and Chemotherapy, Vol. 36, Issue 11
TLSMD web server for the generation of multi-group TLS models
journal, January 2006
- Painter, Jay; Merritt, Ethan A.
- Journal of Applied Crystallography, Vol. 39, Issue 1
Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance
journal, November 1998
- Huang, H.
- Science, Vol. 282, Issue 5394
The HIV therapy market
journal, June 2016
- Gubernick, Steven I.; Félix, Nuno; Lee, Dolim
- Nature Reviews Drug Discovery, Vol. 15, Issue 7
Nucleotide-dependent conformational change governs specificity and analog discrimination by HIV reverse transcriptase
journal, April 2010
- Kellinger, Matthew W.; Johnson, Kenneth A.
- Proceedings of the National Academy of Sciences, Vol. 107, Issue 17
Structural basis for the D-stereoselectivity of human DNA polymerase β
journal, April 2017
- Vyas, Rajan; Reed, Andrew J.; Raper, Austin T.
- Nucleic Acids Research, Vol. 45, Issue 10
The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro.
journal, January 1992
- Coates, J. A.; Cammack, N.; Jenkinson, H. J.
- Antimicrobial Agents and Chemotherapy, Vol. 36, Issue 1
Toxicity of Antiretroviral Nucleoside and Nucleotide Analogues: Is Mitochondrial Toxicity the Only Mechanism?
journal, January 2000
- Moyle, Graeme
- Drug Safety, Vol. 23, Issue 6
Mitochondrial toxicity of nrti antiviral drugs: an integrated cellular perspective
journal, October 2003
- Lewis, William; Day, Brian J.; Copeland, William C.
- Nature Reviews Drug Discovery, Vol. 2, Issue 10
DNA Polymerase Fidelity: Kinetics, Structure, and Checkpoints †
journal, November 2004
- Joyce, Catherine M.; Benkovic, Stephen J.
- Biochemistry, Vol. 43, Issue 45
Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography
journal, August 2017
- Chan, Albert H.; Lee, Won-Gil; Spasov, Krasimir A.
- Proceedings of the National Academy of Sciences, Vol. 114, Issue 36
Long term adverse effects related to nucleoside reverse transcriptase inhibitors: Clinical impact of mitochondrial toxicity
journal, January 2009
- Maagaard, Anne; Kvale, Dag
- Scandinavian Journal of Infectious Diseases, Vol. 41, Issue 11-12
Structures of HIV-1 RT-RNA/DNA ternary complexes with dATP and nevirapine reveal conformational flexibility of RNA/DNA: insights into requirements for RNase H cleavage
journal, May 2014
- Das, Kalyan; Martinez, Sergio E.; Bandwar, Rajiv P.
- Nucleic Acids Research, Vol. 42, Issue 12
Optimal description of a protein structure in terms of multiple groups undergoing TLS motion
journal, March 2006
- Painter, Jay; Merritt, Ethan A.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 4
Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection
journal, February 2017
- Kudalkar, Shalley N.; Beloor, Jagadish; Chan, Albert H.
- Molecular Pharmacology, Vol. 91, Issue 4
Crystal engineering of HIV-1 reverse transcriptase for structure-based drug design
journal, August 2008
- Bauman, Joseph D.; Das, Kalyan; Ho, William C.
- Nucleic Acids Research, Vol. 36, Issue 15
Visualizing the Molecular Interactions of a Nucleotide Analog, GS-9148, with HIV-1 Reverse Transcriptase–DNA Complex
journal, April 2010
- Lansdon, Eric B.; Samuel, Dharmaraj; Lagpacan, Leanna
- Journal of Molecular Biology, Vol. 397, Issue 4
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Matthews coefficient probabilities: Improved estimates for unit cell contents of proteins, DNA, and protein-nucleic acid complex crystals
journal, September 2003
- Kantardjieff, Katherine A.; Rupp, Bernhard
- Protein Science, Vol. 12, Issue 9
Structural Insights into the Post-Chemistry Steps of Nucleotide Incorporation Catalyzed by a DNA Polymerase
journal, December 2016
- Reed, Andrew J.; Vyas, Rajan; Raper, Austin T.
- Journal of the American Chemical Society, Vol. 139, Issue 1
A mechanism for all polymerases
journal, January 1998
- Steitz, Thomas A.
- Nature, Vol. 391, Issue 6664
Structural basis of HIV inhibition by translocation-defective RT inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)
journal, August 2016
- Salie, Zhe Li; Kirby, Karen A.; Michailidis, Eleftherios
- Proceedings of the National Academy of Sciences, Vol. 113, Issue 33
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Genetic risks of antiviral nucleoside analogues – a survey
journal, February 2001
- Wutzler, Peter; Thust, Rudolf
- Antiviral Research, Vol. 49, Issue 2
Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP
journal, January 2000
- Vaccaro, J. A.; Parnell, K. M.; Terezakis, S. A.
- Antimicrobial Agents and Chemotherapy, Vol. 44, Issue 1
Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors
journal, July 2018
- Yang, Yang; Kang, Dongwei; Nguyen, Laura A.
- eLife, Vol. 7
Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA
journal, December 2002
- Sarafianos, S. G.
- The EMBO Journal, Vol. 21, Issue 23