A general strategy to inhibit serine protease by targeting its autolysis loop
Open Access
- 8 January 2021
- journal article
- review article
- Published by Wiley in The FASEB Journal
- Vol. 35 (2), e21259
- https://doi.org/10.1096/fj.202002139rr
Abstract
Serine proteases are a large family of enzymes critical for multiple physiological processes, and proven diagnostic and therapeutic targets in several clinical indications. The high similarity of active sites among different serine proteases posts a challenge to reach high selectivity for inhibitors of serine proteases targeting at the active site. Here, we demonstrated that one particular surface loop on serine proteases (autolysis loop) can be used to regulate their catalytic activity, through surveying the recent works including ours, and such an approach can reach high specificity. The autolysis loop is highly variable among different serine proteases, explaining the high specificity of inhibitors targeting the autolysis loop. We also outline the structural origin that links the perturbation of the autolysis loop and the inhibition of protease activity. Thus, the autolysis loop appears to be a highly sensitive allosteric site and can be used as a general handle to develop pharmacological agents to intervene with the activities of serine proteases in, eg, blood coagulation.Keywords
Funding Information
- Natural Science Foundation of Fujian Province (2018J01897, 2018J01729)
- National Natural Science Foundation of China (82070142, 22077016)
This publication has 62 references indexed in Scilit:
- The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER databaseNucleic Acids Research, 2017
- Serine peptidases: Classification, structure and functionCellular and Molecular Life Sciences, 2008
- In search of partners: linking extracellular proteases to substratesNature Reviews Molecular Cell Biology, 2007
- The catalytic triad of serine peptidasesCellular and Molecular Life Sciences, 2005
- Serine Protease Mechanism and SpecificityChemical Reviews, 2002
- Strategies for the inhibition of serine proteasesCellular and Molecular Life Sciences, 2001
- Unique fold and active site in cytomegalovirus proteaseNature, 1996
- Three-dimensional structure of human cytomegalovirus proteaseNature, 1996
- Dissecting the catalytic triad of a serine proteaseNature, 1988
- Structural basis of the activation and action of trypsinAccounts of Chemical Research, 1978