Summary information and primary citation
- PDB-id
-
6uit;
DSSR-derived features in text and
JSON formats
- Class
- viral protein
- Method
- X-ray (2.81 Å)
- Summary
- Hiv-1 wild-type reverse transcriptase-DNA complex with
dctp
- Reference
-
Hung M, Tokarsky EJ, Lagpacan L, Zhang L, Suo Z, Lansdon
EB (2019): "Elucidating
molecular interactions ofL-nucleotides with HIV-1 reverse
transcriptase and mechanism of M184V-caused drug
resistance." Commun Biol,
2, 469. doi: 10.1038/s42003-019-0706-x.
- Abstract
- 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/<i>K</i> <sub>d</sub>) 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) <i>K</i>
<sub>d</sub> for the
<i>L</i>-nucleotides and moderately higher
(>9-fold) <i>K</i>
<sub><i>d</i></sub> for the
<i>D</i>-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.
