8D3S

HIV-1 Integrase Catalytic Core Domain F185H Mutant Complexed with BKC-110

8D3S の概要

• エントリーDOI: 10.2210/pdb8d3s/pdb
• 分子名称: Integrase, (2S)-tert-butoxy{4-(4-chlorophenyl)-2,6-dimethyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}acetic acid (3 entities in total)
• 機能のキーワード: integrase, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18402.43

構造登録者

Dinh, T.,Kvaratskhelia, M. (登録日: 2022-06-01, 公開日: 2023-06-14, 最終更新日: 2024-10-09)

主引用文献

Dinh, T.,Tber, Z.,Rey, J.S.,Mengshetti, S.,Annamalai, A.S.,Haney, R.,Briganti, L.,Amblard, F.,Fuchs, J.R.,Cherepanov, P.,Kim, K.,Schinazi, R.F.,Perilla, J.R.,Kim, B.,Kvaratskhelia, M.
The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.
Biorxiv, 2024

PubMed Abstract: Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. While both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCD + PIR complex. Consequently, full-length IN was substantially less susceptible to the PIR induced hyper-multimerization than the WT protein, and HIV-1 conferred >150-fold resistance to the inhibitor compared to the WT virus. By rationally modifying PIR we have developed its analog EKC110, which readily induced hyper-multimerization of IN and was ~14-fold more potent against HIV-1 than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.

PubMed: 38328097
DOI: 10.1101/2024.01.26.577387

実験手法

X-RAY DIFFRACTION (1.84 Å)