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

This is a non-PDB format compatible entry.

Summary for 9MXR

• Entry DOI: 10.2210/pdb9mxr/pdb
• EMDB information: 48719
• Descriptor: Reverse transcriptase/ribonuclease H, 5-{2-[2-(2-oxo-4-sulfanylidene-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}naphthalene-2-carbonitrile (2 entities in total)
• Functional Keywords: reverse transcriptase, antiviral, drug design, hiv-1, viral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 130248.16

Authors

Hollander, K.,Devarkar, S.C.,Tang, S.,Ma, S.,Xiong, Y.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2025-01-20, release date: 2025-09-10, Last modification date: 2025-09-17)

Primary citation

Hollander, K.,Devarkar, S.C.,Tang, S.,Tiwari, R.,Ma, S.,Lee, W.G.,Denn, E.,Wang, Q.,Spasov, K.A.,Robbins, J.A.,Frey, K.M.,Jorgensen, W.L.,Xiong, Y.,Shan, L.,Anderson, K.S.
Mechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells.
Npj Drug Discov, 2:22-22, 2025

PubMed Abstract: 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.

PubMed: 40904837
DOI: 10.1038/s44386-025-00025-2

Experimental method

ELECTRON MICROSCOPY (3.05 Å)