36CW

HIV-1 reverse transcriptase (F227C) in complex with DNAddG Aptamer and unincorporated ISL-triphosphate

Summary for 36CW

• Entry DOI: 10.2210/pdb36cw/pdb
• Related: 36BT 36CP
• EMDB information: 77393
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, DNAddG (38-MER), ... (6 entities in total)
• Functional Keywords: reverse transcriptase, dna polymerase activity, nucleoside reverse transcriptase inhibitor, hiv-1, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 3
• Total formula weight: 130223.56

Authors

Hecksel, C.W.,Walker, S.N.,Klein, D.J. (deposition date: 2026-06-01, release date: 2026-09-02, Last modification date: 2026-09-23)

Primary citation

Hecksel, C.W.,Walker, S.N.,Raheem, I.,Asante-Appiah, E.,Calero, G.,Diamond, T.L.,Gabelli, S.B.,Gomez-Llorente, Y.,Hayes, R.P.,Tummala, S.,Vergara, S.,Klein, D.J.
Allosteric Crosstalk between Inhibitor Binding Sites Drives Enhanced Islatravir Susceptibility in F227C HIV-1 Reverse Transcriptase.
Acs Infect Dis., 12:3179-3190, 2026

PubMed Abstract: Doravirine (DOR) and islatravir (ISL) are inhibitors of human immunodeficiency virus type 1 (HIV-1) replication that block the viral reverse transcriptase (RT) by distinct mechanisms. The combination has demonstrated efficacy in Phase 3 clinical studies in both virologically suppressed and treatment-naïve people living with HIV-1 and has the potential to mitigate the emergence of resistance-associated mutations through complementary virological profiles. RT bearing a single point mutation, F227C, is associated with resistance to DOR, yet is hypersusceptible to ISL. Here, we report cryoEM structures of islatravir triphosphate (ISL-TP) bound to wild-type (WT) RT and F227C RT. Comparison with the corresponding ISL-TP and dATP-bound WT RT structures reveals that the F227C mutation induces an unexpected conformational change in a loop of the palm domain that is positioned to gate substrate access, providing a structural basis for ISL hypersusceptibility.

PubMed: 42725963
DOI: 10.1021/acsinfecdis.6c00431

Experimental method

ELECTRON MICROSCOPY (1.9 Å)