7AIF

HIV-1 REVERSE TRANSCRIPTASE COMPLEX WITH DNA AND L-GLUTAMATE TENOFOVIR WITH BOUND MANGANESE

Summary for 7AIF

• Entry DOI: 10.2210/pdb7aif/pdb
• Descriptor: Gag-Pol polyprotein, DNA (5'-D(P*GP*GP*TP*CP*GP*GP*CP*GP*CP*CP*CP*GP*AP*AP*CP*AP*GP*GP*GP*AP*CP*TP*G)-3'), DNA (5'-D(*CP*AP*GP*TP*CP*CP*CP*TP*GP*TP*TP*CP*GP*GP*(MRG)P*CP*GP*CP*CP*(DDG))-3'), ... (7 entities in total)
• Functional Keywords: reverse transcriptase, rt inhibitor complex, tenofovir analog, rt-dna complex, transferase
• Biological source: Human immunodeficiency virus type 1 BH10; More
• Total number of polymer chains: 8
• Total formula weight: 258891.51

Authors

Gu, W.,Martinez, S.E.,Nguyen, H.,Xu, H.,Herdewijn, P.,de Jonghe, S.,Das, K. (deposition date: 2020-09-27, release date: 2021-01-13, Last modification date: 2024-01-31)

Primary citation

Gu, W.,Martinez, S.,Nguyen, H.,Xu, H.,Herdewijn, P.,De Jonghe, S.,Das, K.
Tenofovir-Amino Acid Conjugates Act as Polymerase Substrates-Implications for Avoiding Cellular Phosphorylation in the Discovery of Nucleotide Analogues.
J.Med.Chem., 64:782-796, 2021

PubMed Abstract: Nucleotide analogues are used for treating viral infections such as HIV, hepatitis B, hepatitis C, influenza, and SARS-CoV-2. To become polymerase substrates, a nucleotide analogue must be phosphorylated by cellular kinases which is rate-limiting. The goal of this study is to develop dNTP/NTP analogues directly from nucleotides. Tenofovir (TFV) analogues were synthesized by conjugating with amino acids. We demonstrate that some conjugates act as dNTP analogues and HIV-1 reverse transcriptase (RT) catalytically incorporates the TFV part as the chain terminator. X-ray structures in complex with HIV-1 RT/dsDNA showed binding of the conjugates at the polymerase active site, however, in different modes in the presence of Mg versus Mn ions. The adaptability of the compounds is seemingly essential for catalytic incorporation of TFV by RT. with a carboxyl sidechain demonstrated the highest incorporation. showed weak incorporation and rather behaved as a dNTP-competitive inhibitor. This result advocates the feasibility of designing NTP/dNTP analogues by chemical substitutions to nucleotide analogues.

PubMed: 33356231
DOI: 10.1021/acs.jmedchem.0c01747

Experimental method

X-RAY DIFFRACTION (2.75 Å)