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TitleMechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells.
Journal, issue, pagesNPJ Drug Discov, Vol. 2, Issue 1, Page 22, Year 2025
Publish dateSep 1, 2025
AuthorsKlarissa Hollander / Swapnil C Devarkar / Su Tang / Ritudhwaj Tiwari / Shumeng Ma / Won Gil Lee / Elizabeth Denn / Qiankun Wang / Krasimir A Spasov / Jake A Robbins / Kathleen M Frey / William L Jorgensen / Yong Xiong / Liang Shan / Karen S Anderson /
PubMed AbstractA strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These ...A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These NNRTIs stimulate dimerization of the Gag-Pol polyprotein, resulting in premature HIV-1 protease (PR) dimerization and cleavage of intracellular CARD8. A unique cell-based high-throughput screen was developed to identify potent compounds activating the CARD8 inflammasome through Gag-Pol dimerization. Our in-house library of NNRTIs was evaluated, including a series of catechol diethers, which are potent, nontoxic antivirals. JLJ648 was identified as a promising dual-function antiviral and Gag-Pol dimerizer. Cryo-EM studies of HIV reverse transcriptase p66 bound to JLJ648 revealed populations of homodimers and, surprisingly, a homotetramer. This novel homotetramer structure resembling an 'infinity knot' revealed two JLJ648-bound homodimers forming an extensive interface and nucleated around a dimer of JLJ648 molecules. Structure-guided mutagenesis studies indicate that Gag-Pol homotetramerization may play a critical role in facilitating PR self-cleavage and triggering pyroptosis.
External linksNPJ Drug Discov / PubMed:40904837 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.37 - 3.85 Å
Structure data

48718

9mxq

EMDB-48718, PDB-9mxq:
Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 Homodimer
Method: EM (single particle) / Resolution: 3.85 Å

48719

9mxr

EMDB-48719: Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 Homodimer in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}naphthalene-2-carbonitrile (JLJ648), a Non-nucleoside Inhibitor
PDB-9mxr: Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 Homodimer in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy] phenoxy}naphthalene-2-carbonitrile (JLJ648), a Non-nucleoside Inhibitor
Method: EM (single particle) / Resolution: 3.05 Å

48720

9mxs

EMDB-48720: Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 Homodimer in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}naphthalene-2-carbonitrile, a Non-nucleoside Inhibitor, with an Additional Pocket of Density
PDB-9mxs: Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 Homodimer in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy] phenoxy}naphthalene-2-carbonitrile, a Non-nucleoside Inhibitor, with an Additional Pocket of Density
Method: EM (single particle) / Resolution: 3.09 Å

48721

9mxt

EMDB-48721, PDB-9mxt:
Cryo-EM Structure of HIV-1 Reverse Transcriptase p66 tetramer in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}naphthalene-2-carbonitrile (JLJ648), a Non-nucleoside Inhibitor
Method: EM (single particle) / Resolution: 3.43 Å

PDB-9mxb:
Crystal Structure of WT HIV-1 Reverse Transcriptase in Complex with 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy] phenoxy}naphthalene-2-carbonitrile (JLJ648), a non-nucleoside inhibitor
Method: X-RAY DIFFRACTION / Resolution: 2.37 Å

Chemicals

ChemComp-CL:
Unknown entry

ChemComp-SO4:
SULFATE ION

PDB-1btu:
PORCINE PANCREATIC ELASTASE COMPLEXED WITH (3S, 4R)-1-TOLUENESULPHONYL-3-ETHYL-AZETIDIN-2-ONE-4-CARBOXYLIC ACID

ChemComp-HOH:
WATER

Source
  • human immunodeficiency virus 1
KeywordsVIRAL PROTEIN / REVERSE TRANSCRIPTASE / ANTIVIRAL / DRUG DESIGN / HIV-1

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