Novel Structural Mechanism of Allosteric Regulation of Aspartic Peptidases via an Evolutionarily Conserved Exosite
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
PubMed
29396291
DOI
10.1016/j.chembiol.2018.01.001
PII: S2451-9456(18)30001-1
Knihovny.cz E-resources
- Keywords
- allosteric inhibitor, aspartic peptidase, crystal structure, exosite, proteolysis,
- MeSH
- Enzyme Activation MeSH
- Allosteric Regulation MeSH
- Catalytic Domain MeSH
- Cathepsin D chemistry metabolism MeSH
- Kinetics MeSH
- Ticks enzymology MeSH
- Hydrogen-Ion Concentration MeSH
- Crystallography, X-Ray MeSH
- Ligands MeSH
- Peptides chemistry metabolism MeSH
- Enzyme Precursors chemistry metabolism MeSH
- Amino Acid Sequence MeSH
- Sequence Alignment MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Names of Substances
- Cathepsin D MeSH
- Ligands MeSH
- Peptides MeSH
- Enzyme Precursors MeSH
Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide. This fragment functions as an effective natural inhibitor of mature IrCD1 that operates in a pH-dependent manner through a unique allosteric inhibition mechanism. The study uncovers the propeptide-binding exosite as a target for the regulation of pepsin-family aspartic peptidases and defines the structural requirements for exosite inhibition.
References provided by Crossref.org
Precursors of Viral Proteases as Distinct Drug Targets
