6UIS
HIV-1 M184V reverse transcriptase-DNA complex with dCTP
Summary for 6UIS
| Entry DOI | 10.2210/pdb6uis/pdb |
| Descriptor | p66 Reverse transcriptase/RNaseH, p51 Reverse transcriptase/RNaseH, Primer DNA, ... (8 entities in total) |
| Functional Keywords | hiv-1 reverse transcriptase nrti polymerase dna complex, viral protein |
| Biological source | Human immunodeficiency virus type 1 group M subtype B (isolate HXB2) (HIV-1) More |
| Total number of polymer chains | 4 |
| Total formula weight | 132722.59 |
| Authors | Lansdon, E.B. (deposition date: 2019-10-01, release date: 2019-12-25, Last modification date: 2023-10-11) |
| Primary citation | Hung, M.,Tokarsky, E.J.,Lagpacan, L.,Zhang, L.,Suo, Z.,Lansdon, E.B. Elucidating molecular interactions ofL-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance. Commun Biol, 2:469-469, 2019 Cited by PubMed 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/) 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) for the -nucleotides and moderately higher (>9-fold) for the -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. PubMed: 31872074DOI: 10.1038/s42003-019-0706-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.74833813248 Å) |
Structure validation
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