ArticleProceedings of the National Academy of Sciences of the United States of America2009
Structure of granzyme C reveals an unusual mechanism of protease autoinhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Conformational Dynamics of Plasmepsin X during Inhibitor Binding.The journal of physical chemistry. B · 2026Article
- Widespread and dynamic expression of granzyme C by skin-resident antiviral T cells.Frontiers in immunology · 2023Article
- CD8αα+MHC Class II+ Cell with the Capacity To Terminate Autoimmune Inflammation Is a Novel Antigen-Presenting NK-like Cell in Rats.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- Direct and indirect mechanisms of KLK4 inhibition revealed by structure and dynamics.Scientific reports · 2016Article
- The iceLogo web server and SOAP service for determining protein consensus sequences.Nucleic acids research · 2015Article
- Conservation of the extended substrate specificity profiles among homologous granzymes across species.Molecular & cellular proteomics : MCP · 2013Article
- The Online Protein Processing Resource (TOPPR): a database and analysis platform for protein processing events.Nucleic acids research · 2013Article
- Selecting protein N-terminal peptides by combined fractional diagonal chromatography.Nature protocols · 2011Article
Corrections and comments
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteases act in important homeostatic pathways and are tightly regulated. Here, we report an unusual structural mechanism of regulation observed by the 2.5-A X-ray crystal structure of the serine protease, granzyme C. Although the active-site triad residues adopt canonical conformations, the oxyanion hole is improperly formed, and access to the primary specificity (S1) pocket is blocked through a reversible rearrangement involving Phe-191. Specifically, a register shift in the 190-strand preceding the active-site serine leads to Phe-191 filling the S1 pocket. Mutation of a unique Glu-Glu motif at positions 192-193 unlocks the enzyme, which displays chymase activity, and proteomic analysis confirms that activity of the wild-type protease can be released through interactions with an appropriate substrate. The 2.5-A structure of the unlocked enzyme reveals unprecedented flexibility in the 190-strand preceding the active-site serine that results in Phe-191 vacating the S1 pocket. Overall, these observations describe a broadly applicable mechanism of protease regulation that cannot be predicted by template-based modeling or bioinformatic approaches alone.
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