@article{2a8e0decff624094baa1084fc905aeb4,
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",
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.",
keywords = "emtricitabine, inhibitor–protein complexes, lamivudine, macromolecular X-ray crystallography, nucleoside reverse transcriptase inhibitors",
author = "Nicole Bertoletti and Chan, {Albert H.} and Schinazi, {Raymond F.} and Yin, {Y. Whitney} and Anderson, {Karen S.}",
note = "Funding Information: information National Institute of Allergy and Infectious Diseases, Grant/Award Numbers: AI134611, AI50409; National Institute of General Medical Sciences, Grant/Award Numbers: GM049551, GM103403, GM111244; DOE Office of Biological and Environmental Research, Grant/Award Number: KP1605010; Brookhaven National Laboratory, Grant/Award Number: DE-SC0012704; Argonne National Laboratory, Grant/Award Number: DE-AC02-06CH11357; Yale Macromolecular X-ray Core Facility, Grant/Award Number: 1S10OD018007-01Gratitude is expressed to the National Institutes of Health (NIH) (Grants GM049551 for KSA and AI134611 for YWY). R.F.S. is funded by the CFAR NIH grant 5P30-AI-50409. We thank Sheida Amiralaei for assisting with the synthesis and characterization of the FTC nucleotides. The authors are grateful to Stefan G. Sarafianos for providing access to the RT construct. This work is based upon research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences (NIGMS) from the NIH (P41 GM103403). Crystals screening was conducted with supports in the Yale Macromolecular X-ray Core Facility (1S10OD018007-01). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. This research used FMX beamline of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under Contract No. DE-SC0012704. The Life Science Biomedical Technology Research resource is primarily supported by the NIH, NIGMS through a Biomedical Technology Research Resource P41 grant (P41 GM111244), and by the DOE Office of Biological and Environmental Research (KP1605010). Publisher Copyright: {\textcopyright} 2019 The Protein Society",
year = "2019",
doi = "10.1002/pro.3681",
language = "English (US)",
volume = "28",
pages = "1664--1675",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "9",
}