ArticleJournal of molecular biology2018
HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites.
Article in Journal of molecular biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Prophage: agent provocateur?Archives of microbiology · 2026Review
- Mechanism and Kinetics of HIV-1 Protease Activation.Viruses · 2024Review
- The human retroviral-like aspartic protease 1 (ASPRV1): From in vitro studies to clinical correlations.The Journal of biological chemistry · 2024Review
- FMO-guided design of darunavir analogs as HIV-1 protease inhibitors.Scientific reports · 2024Article
- Comprehending the Structure, Dynamics, and Mechanism of Action of Drug-Resistant HIV Protease.ACS omega · 2023Review
- Sequence dependencies and biophysical features both govern cleavage of diverse cut-sites by HIV protease.Protein science : a publication of the Protein Society · 2022Article
- Stephan Oroszlan and the Proteolytic Processing of Retroviral Proteins: Following A Pro.Viruses · 2021Review
- Review
- CARD8 is an inflammasome sensor for HIV-1 protease activity.Science (New York, N.Y.) · 2021Article
- AnACS catalysis · 2019Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Retroviral proteases (PRs) have a unique specificity that allows cleavage of sites with or without a P1' proline. A P1' proline is required at the MA/CA cleavage site due to its role in a post-cleavage conformational change in the capsid protein. However, the HIV-1 PR prefers to have large hydrophobic amino acids flanking the scissile bond, suggesting that PR recognizes two different classes of substrate sequences. We analyzed the cleavage rate of over 150 combinations of six different HIV-1 cleavage sites to explore rate determinants of cleavage. We found that cleavage rates are strongly influenced by the two amino acids flanking the amino acids at the scissile bond (P2-P1/P1'-P2'), with two complementary sets of rules. When P1' is proline, the P2 side chain interacts with a polar region in the S2 subsite of the PR, while the P2' amino acid interacts with a hydrophobic region of the S2' subsite. When P1' is not proline, the orientations of the P2 and P2' side chains with respect to the scissile bond are reversed; P2 residues interact with a hydrophobic face of the S2 subsite, while the P2' amino acid usually engages hydrophilic amino acids in the S2' subsite. These results reveal that the HIV-1 PR has evolved bi-functional S2 and S2' subsites to accommodate the steric effects imposed by a P1' proline on the orientation of P2 and P2' substrate side chains. These results also suggest a new strategy for inhibitor design to engage the multiple specificities in these subsites.
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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.