ArticleProtein science : a publication of the Protein Society2000
Systematic mutational analysis of the active-site threonine of HIV-1 proteinase: rethinking the "fireman's grip" hypothesis.
Article in Protein science : a publication of the Protein Society, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 39 citations in OpenAlex.
- The human retroviral-like aspartic protease 1 (ASPRV1): From in vitro studies to clinical correlations.The Journal of biological chemistry · 2024Review
- Precursors of Viral Proteases as Distinct Drug Targets.Viruses · 2021Review
- Functional Study of the Retrotransposon-Derived Human PEG10 Protease.International journal of molecular sciences · 2020Article
- Dimer Interface Organization is a Main Determinant of Intermonomeric Interactions and Correlates with Evolutionary Relationships of Retroviral and Retroviral-Like Ddi1 and Ddi2 Proteases.International journal of molecular sciences · 2020Article
- Article
- GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants.Antimicrobial agents and chemotherapy · 2018Article
- Article
- Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity.Retrovirology · 2012Article
- Drug-resistant molecular mechanism of CRF01_AE HIV-1 protease due to V82F mutation.Journal of computer-aided molecular design · 2009Article
- Enzymatic and structural analysis of the I47A mutation contributing to the reduced susceptibility to HIV protease inhibitor lopinavir.Protein science : a publication of the Protein Society · 2008Article
- Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region.Journal of virology · 2008Article
- Evidence that the Bacillus subtilis SpoIIGA protein is a novel type of signal-transducing aspartic protease.The Journal of biological chemistry · 2008Article
- Effect of the active site D25N mutation on the structure, stability, and ligand binding of the mature HIV-1 protease.The Journal of biological chemistry · 2008Article
- Design of a trans protease lentiviral packaging system that produces high titer virus.Retrovirology · 2007Article
- Kinetics of the dimerization of retroviral proteases: the "fireman's grip" and dimerization.Protein science : a publication of the Protein Society · 2003Article
- Importance of the N terminus of rous sarcoma virus protease for structure and enzymatic function.Journal of virology · 2001Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aspartic proteinases share a conserved network of hydrogen bonds (termed "fireman's grip"), which involves the hydroxyl groups of two threonine residues in the active site Asp-Thr-Gly triplets (Thr26 in the case of human immunodeficiency virus type 1 (HIV-1) PR). In the case of retroviral proteinases (PRs), which are active as symmetrical homodimers, these interactions occur at the dimer interface. For a systematic analysis of the "fireman's grip," Thr26 of HIV-1 PR was changed to either Ser, Cys, or Ala. The variant enzymes were tested for cleavage of HIV-1 derived peptide and polyprotein substrates. PR(T26S) and PR(T26C) showed similar or slightly reduced activity compared to wild-type HIV-1 PR, indicating that the sulfhydryl group of cysteine can substitute for the hydroxyl of the conserved threonine in this position. PR(T26A), which lacks the "fireman's grip" interaction, was virtually inactive and was monomeric in solution at conditions where wild-type PR exhibited a monomer-dimer equilibrium. All three mutations had little effect when introduced into only one chain of a linked dimer of HIV-1 PR. In this case, even changing both Thr residues to Ala yielded residual activity suggesting that the "fireman's grip" is not essential for activity but contributes significantly to dimer formation. Taken together, these results indicate that the "fireman's grip" is crucial for stabilization of the retroviral PR dimer and for overall stability of the enzyme.
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