7XJ4

Crystal structure of engineered HIV-1 Reverse Transcriptase RNase H domain complexed with nitrofuran methoxy(methoxycarbonyl)phenyl ester

Summary for 7XJ4

• Entry DOI: 10.2210/pdb7xj4/pdb
• Descriptor: Reverse Transcriptase RNase H domain, MANGANESE (II) ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: ribonuclease, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 1
• Total formula weight: 17497.77

Authors

Lu, H.,Komukai, Y.,Usami, K.,Guo, Y.,Qiao, X.,Nukaga, M.,Hoshino, T. (deposition date: 2022-04-15, release date: 2022-04-27, Last modification date: 2023-11-29)

Primary citation

Lu, H.,Komukai, Y.,Usami, K.,Guo, Y.,Qiao, X.,Nukaga, M.,Hoshino, T.
Computational and Crystallographic Analysis of Binding Structures of Inhibitory Compounds for HIV-1 RNase H Activity.
J.Chem.Inf.Model., 62:6762-6774, 2022

PubMed Abstract: Chemotherapy of human immunodeficiency virus type-1 (HIV-1) has significantly developed over the last three decades. The emergence of drug-resistant variants is, however, still a severe problem. The RNase H activity of HIV-1 reverse transcriptase is an attractive target for a new class of antiviral drugs because there is no approved inhibitor. The nitro-furan-carbonyl and nitro-thiophene-carbonyl groups are potent scaffolds for the HIV-1 RNase H inhibitor. In this work, the binding structures of six inhibitory compounds were obtained by X-ray crystal analysis in a complex with a recombinant protein of HIV-1 RNase H domain. Every inhibitory compound was found to be bound to the catalytic site with the furan- or thiophene-ring coordinated to two divalent metal ions at the binding pocket. All the atoms in nitro, furan, carbonyl, and two metals were aligned in the nitro-furan derivatives. The straight line connecting nitro and carboxyl groups was parallel to the plane made by two metal ions and a furan O atom. The binding modes of the nitro-thiophene derivatives were slightly different from those of the nitro-furan ones. The nitro and carbonyl groups deviated from the plane made by two metals and a thiophene S atom. Molecular dynamics simulations suggested that the furan O or thiophene S atom and carbonyl O atom were firmly coordinated to the metal ions. The simulations made the planar nitro-furan moiety well aligned to the line connecting the two metal ions. In contrast, the nitro-thiophene derivatives were displaced from the initial positions after the simulations. The computational findings will be a sound basis for developing potent inhibitors for HIV-1 RNase H activity.

PubMed: 36184946
DOI: 10.1021/acs.jcim.2c00537

Experimental method

X-RAY DIFFRACTION (1.8 Å)