Summary information and primary citation
- PDB-id
-
6wpf;
DSSR-derived features in text and
JSON formats
- Class
- transferase-DNA
- Method
- X-ray (2.53 Å)
- Summary
- Structure of hiv-1 reverse transcriptase (rt) in
complex with dsDNA and d4t
- Reference
-
Bertoletti N, Chan AH, Schinazi RF, Anderson KS (2020):
"Post-Catalytic
Complexes with Emtricitabine or Stavudine and HIV-1
Reverse Transcriptase Reveal New Mechanistic Insights for
Nucleotide Incorporation and Drug Resistance."
Molecules, 25. doi: 10.3390/molecules25204868.
- Abstract
- 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.
