ArticleProceedings of the National Academy of Sciences of the United States of America2017
Binding kinetics and substrate selectivity in HIV-1 protease-Gag interactions probed at atomic resolution by chemical exchange NMR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- Inhibitors of HIV-1 maturation modulate conformational dynamics and heterogeneity of the immature Gag lattice.bioRxiv : the preprint server for biology · 2026Article
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- Identifying Conserved Regions in HIV-1 Proteins by Entropy Analysis of Sequence Variability.International journal of molecular sciences · 2026Article
- Molecular mechanisms of protease precursor autoprocessing of RNA viruses: a comprehensive review.Virology journal · 2026Review
- Substrate specificity in a designed RAS-targeting protease is coupled to active site and distal motions.bioRxiv : the preprint server for biology · 2026Article
- Dock-and-lock binding of SxIP ligands is required for stable and selective EB1 interactions.eLife · 2025Article
- Unraveling structural transitions and kinetics along the fold-switching pathway of the RfaH C-terminal domain using exchange-based NMR.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural and Functional Studies on HIV Protease: Mechanism of Action, Subtypes, Inhibitors, and Drug Resistance.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Mechanism and Kinetics of HIV-1 Protease Activation.Viruses · 2024Review
- A Transient, Excited Species of the Autoinhibited α-State of the Bacterial Transcription Factor RfaH May Represent an Early Intermediate on the Fold-Switching Pathway.Biochemistry · 2024Article
- Quantitative Characterization of Chain-Flipping of Acyl Carrier Protein ofJournal of the American Chemical Society · 2024Article
- Molecular dynamics simulations of HIV-1 matrix-membrane interactions at different stages of viral maturation.Biophysical journal · 2024Article
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- HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics.Journal of molecular graphics & modelling · 2022Article
- Quantitative NMR analysis of the kinetics of prenucleation oligomerization and aggregation of pathogenic huntingtin exon-1 protein.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Multiple Molecular Dynamics Simulations and Energy Analysis Unravel the Dynamic Properties and Binding Mechanism of Mutants HIV-1 Protease with DRV and CA-p2.Microbiology spectrum · 2022Article
- NMR methods for exploring 'dark' states in ligand binding and protein-protein interactions.Progress in nuclear magnetic resonance spectroscopy · 2022Review
- Kinetics of Bovine leukemia virus aspartic protease reveals its dimerization and conformational change.PloS one · 2022Article
- The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.Frontiers in molecular biosciences · 2022Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The conversion of immature noninfectious HIV-1 particles to infectious virions is dependent upon the sequential cleavage of the precursor group-specific antigen (Gag) polyprotein by HIV-1 protease. The precise mechanism whereby protease recognizes distinct Gag cleavage sites, located in the intrinsically disordered linkers connecting the globular domains of Gag, remains unclear. Here, we probe the dynamics of the interaction of large fragments of Gag and various variants of protease (including a drug resistant construct) using Carr-Purcell-Meiboom-Gill relaxation dispersion and chemical exchange saturation transfer NMR experiments. We show that the conformational dynamics within the flaps of HIV-1 protease that form the lid over the catalytic cleft play a significant role in substrate specificity and ordered Gag processing. Rapid interconversion between closed and open protease flap conformations facilitates the formation of a transient, sparsely populated productive complex between protease and Gag substrates. Flap closure traps the Gag cleavage sites within the catalytic cleft of protease. Modulation of flap opening through protease-Gag interactions fine-tunes the lifetime of the productive complex and hence the likelihood of Gag proteolysis. A productive complex can also be formed in the presence of a noncognate substrate but is short-lived owing to lack of optimal complementarity between the active site cleft of protease and the substrate, resulting in rapid flap opening and substrate release, thereby allowing protease to differentiate between cognate and noncognate substrates.
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