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

Bertoletti, Nicole; Chan, Albert H.; Schinazi, Raymond F.; Anderson, Karen S.

doi:10.3390/molecules25204868

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

DOI:https://doi.org/10.3390/molecules25204868· OSTI ID:1691541

^[1]; Chan, Albert H. ^[1]; Schinazi, Raymond F. ^[2]; Anderson, Karen S. ^[1]

Yale Univ., New Haven, CT (United States)
Yale Univ., New Haven, CT (United States); Emory Univ., Atlanta, GA (United States). Lab. of Biochemical Pharmacology, Center for AIDS Research

Human immunodeficiency virus 1 (HIV-1) infection is a global health issue since neither a cure nor a vaccine is available. However, the highly active antiretroviral therapy (HAART) has improved the life expectancy for patients with acquired immunodeficiency syndrome (AIDS). Nucleoside reverse transcriptase inhibitors (NRTIs) are in almost all HAART and target reverse transcriptase (RT), an essential enzyme for the virus. Even though NRTIs are highly effective, they have limitations caused by RT resistance. The main mechanisms of RT resistance to NRTIs are discrimination and excision. Understanding the molecular mechanisms for discrimination and excision are essential to develop more potent and selective NRTIs. Using protein X-ray crystallography, we determined the first crystal structure of RT in its post-catalytic state in complex with emtricitabine, (-)FTC or stavudine (d4T). Our structural studies provide the framework for understanding how RT discriminates between NRTIs and natural nucleotides, and for understanding the requirement of (-)FTC to undergo a conformation change for successful incorporation by RT. The crystal structure of RT in post-catalytic complex with d4T provides a “snapshot” for considering the possible mechanism of how RT develops resistance for d4T via excision. The findings reported herein will contribute to the development of next generation NRTIs.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1691541

Alternate ID(s):: OSTI ID: 1760499

Journal Information:: Molecules, Journal Name: Molecules Journal Issue: 20 Vol. 25; ISSN 1420-3049

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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