Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance
- Resource Type
- Authors
- Magdeleine Hung; E. John Tokarsky; Leanna Lagpacan; Lijun Zhang; Zucai Suo; Eric B. Lansdon
- Source
- Communications Biology, Vol 2, Iss 1, Pp 1-12 (2019)
- Subject
- 0303 health sciences
03 medical and health sciences
0302 clinical medicine
lcsh:Biology (General)
Medicine (miscellaneous)
virus diseases
General Agricultural and Biological Sciences
lcsh:QH301-705.5
030217 neurology & neurosurgery
General Biochemistry, Genetics and Molecular Biology
3. Good health
030304 developmental biology
- Language
- English
- ISSN
- 2399-3642
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/Kd) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (−)-FTC-TP and (−)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3′-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold) Kd for the L-nucleotides and moderately higher (>9-fold) Kd 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.