ArticleNature communications2021
Sliding of HIV-1 reverse transcriptase over DNA creates a transient P pocket - targeting P-pocket by fragment screening.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Who cites it
7 citing papers in PubMed, 9 citations in OpenAlex.
- Discovery and Cryo-EM-Guided Development of a Neuropilin-2-Binding Aptamer for Receptor Antagonism.Journal of the American Chemical Society · 2026Article
- Structural basis of deoxynucleotide addition by HIV-1 RT during reverse transcription.Nature communications · 2024Article
- Discovery of Novel Amino Acids (Analogues)-Substituted Thiophene[3,2-International journal of molecular sciences · 2024Article
- Structural Insights into Protein-Aptamer Recognitions Emerged from Experimental and Computational Studies.International journal of molecular sciences · 2023Review
- Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase.Molecules (Basel, Switzerland) · 2022Article
- Cryo-EM structures of wild-type and E138K/M184I mutant HIV-1 RT/DNA complexed with inhibitors doravirine and rilpivirine.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies.Viruses · 2022Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.