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

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

Journal Article · Fri Dec 13 00:00:00 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 ^[1]; Zhang, Lijun ^[1]; Suo, Zucai ^[3];

^[1]

Gilead Sciences, Inc., Foster City, CA (United States)
The Ohio State Univ., Columbus, OH (United States). The Ohio State Biophysics Program
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.}

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

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1624535

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

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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