ArticleProceedings of the National Academy of Sciences of the United States of America2004
Communication between the active sites and dimer interface of a herpesvirus protease revealed by a transition-state inhibitor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 46 citations in OpenAlex.
- Antibody reveals conformational latch regulating dimerization in β- and γ-herpesvirus proteases.Nature communications · 2026Article
- Antibody Reveals Conformational Latch Controlling Herpesvirus Proteases.bioRxiv : the preprint server for biology · 2025Article
- Enzyme kinetics model for the coronavirus main protease including dimerization and ligand binding.Biophysical journal · 2025Article
- Article
- The effect of dimerization and ligand binding on the dynamics of Kaposi's sarcoma-associated herpesvirus protease.Proteins · 2022Article
- Fragment-Based Protein-Protein Interaction Antagonists of a Viral Dimeric Protease.ChemMedChem · 2016Article
- Computational Studies of Benzoxazinone Derivatives as Antiviral Agents against Herpes Virus Type 1 Protease.Molecules (Basel, Switzerland) · 2015Article
- Current and potential treatments for ubiquitous but neglected herpesvirus infections.Chemical reviews · 2014Review
- Broad-spectrum allosteric inhibition of herpesvirus proteases.Biochemistry · 2014Article
- Mutational analysis of the Pseudomonas aeruginosa myovirus KZ morphogenetic protease gp175.Journal of virology · 2013Article
- Activity-based protein profiling of host-virus interactions.Trends in biotechnology · 2012Review
- A screening strategy for trapping the inactive conformer of a dimeric enzyme with a small molecule inhibitor.Methods in molecular biology (Clifton, N.J.) · 2012Article
- Cytomegalovirus capsid protease: biological substrates are cleaved more efficiently by full-length enzyme (pUL80a) than by the catalytic domain (assemblin).Journal of virology · 2011Article
- Maturation mechanism of severe acute respiratory syndrome (SARS) coronavirus 3C-like proteinase.The Journal of biological chemistry · 2010Article
- Allosteric regulation of protease activity by small molecules.Molecular bioSystems · 2010Review
- Inhibition of a viral enzyme by a small-molecule dimer disruptor.Nature chemical biology · 2009Article
- Using specificity to strategically target proteases.Bioorganic & medicinal chemistry · 2009Review
- Positional scanning synthetic combinatorial libraries for substrate profiling.Methods in molecular biology (Clifton, N.J.) · 2009Article
- Substrate modulation of enzyme activity in the herpesvirus protease family.Journal of molecular biology · 2007Article
- Enzymatic activities of human cytomegalovirus maturational protease assemblin and its precursor (pPR, pUL80a) are comparable: [corrected] maximal activity of pPR requires self-interaction through its scaffolding domain.Journal of virology · 2007Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Structurally diverse organophosphonate inhibitors targeting the active site of the enzyme were used to investigate the relationship of the active site and the dimer interface of wild-type protease in solution. Positional scanning synthetic combinatorial libraries revealed Kaposi's sarcoma-associated herpesvirus protease to be highly specific, even at sites distal to the peptide bond undergoing hydrolysis. Specificity results were used to synthesize a hexapeptide diphenylphosphonate inhibitor of Kaposi's sarcoma-associated herpesvirus protease. The transition state analog inhibitors covalently phosphonylate the active site serine, freezing the enzyme structure during catalysis. An NMR-based assay was developed to monitor the native monomer-dimer equilibrium in solution and was used to demonstrate the effect of protease inhibition on the quaternary structure of the enzyme. NMR, circular dichroism, and size exclusion chromatography analysis showed that active site inhibition strongly regulates the binding affinity of the monomer-dimer equilibrium at the spatially separate dimer interface of the protease, shifting the equilibrium to the dimeric form of the enzyme. Furthermore, inhibitor studies revealed that the catalytic cycles of the spatially separate active sites are independent. These results (i) provide direct evidence that peptide bond hydrolysis is integrally linked to the quaternary structure of the enzyme, (ii) establish a molecular mechanism of protease activation and stabilization during catalysis, and (iii) highlight potential implications of substoichiometric inhibition of the viral protease in developing herpesviral therapeutics.
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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.