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Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket - targeting P-pocket by fragment screening.

Singh AK, Martinez SE, Gu W, Nguyen H, Schols D, Herdewijn P, De Jonghe S, Das K
Nat Commun 12 7127 (2021)
Related entries: 7oxq, 7oz2, 7oz5, 7p15

Cited: 4 times
EuropePMC logo PMID: 34880240

Abstract

HIV-1 reverse transcriptase (RT) slides over an RNA/DNA or dsDNA substrate while copying the viral RNA to a proviral DNA. We report a crystal structure of RT/dsDNA complex in which RT overstepped the primer 3'-end of a dsDNA substrate and created a transient P-pocket at the priming site. We performed a high-throughput screening of 300 drug-like fragments by X-ray crystallography that identifies two leads that bind the P-pocket, which is composed of structural elements from polymerase active site, primer grip, and template-primer that are resilient to drug-resistance mutations. Analogs of a fragment were synthesized, two of which show noticeable RT inhibition. An engineered RT/DNA aptamer complex could trap the transient P-pocket in solution, and structures of the RT/DNA complex were determined in the presence of an inhibitory fragment. A synthesized analog bound at P-pocket is further analyzed by single-particle cryo-EM. Identification of the P-pocket within HIV RT and the developed structure-based platform provide an opportunity for the design new types of polymerase inhibitors.

Reviews - 7ozw mentioned but not cited (1)

  1. Structural Insights into Protein-Aptamer Recognitions Emerged from Experimental and Computational Studies. Troisi R, Balasco N, Autiero I, Vitagliano L, Sica F. Int J Mol Sci 24 16318 (2023)


Reviews citing this publication (1)

  1. Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies. Singh AK, Das K. Viruses 14 1027 (2022)

Articles citing this publication (2)

  1. Cryo-EM structures of wild-type and E138K/M184I mutant HIV-1 RT/DNA complexed with inhibitors doravirine and rilpivirine. Singh AK, De Wijngaert B, Bijnens M, Uyttersprot K, Nguyen H, Martinez SE, Schols D, Herdewijn P, Pannecouque C, Arnold E, Das K. Proc Natl Acad Sci U S A 119 e2203660119 (2022)
  2. Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase. Wang Y, Wang A, Wang J, Wu X, Sun Y, Wu Y. Molecules 27 7348 (2022)


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