6UIT

HIV-1 wild-type reverse transcriptase-DNA complex with dCTP

6UIT の概要

• エントリーDOI: 10.2210/pdb6uit/pdb
• 分子名称: p66 Reverse transcriptase/RNaseH, p51 Reverse transcriptase/RNaseH, DNA primer, ... (8 entities in total)
• 機能のキーワード: hiv-1 reverse transcriptase nrti polymerase dna complex, viral protein
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate HXB2) (HIV-1); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132858.48

構造登録者

Lansdon, E.B. (登録日: 2019-10-01, 公開日: 2019-12-25, 最終更新日: 2023-10-11)

主引用文献

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

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: 31872074
DOI: 10.1038/s42003-019-0706-x

実験手法

X-RAY DIFFRACTION (2.80607409399 Å)