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Substrate recognition by proteinases
S J Hubbard1, J M Thornton, S F Campbell
1Department of Biochemistry and Molecular Biology, University College, London, UK.
Faraday Discussions
|January 1, 1992
Summary
Serine proteinase inhibitors and substrates bind differently to proteinases. Modeling suggests limited proteolytic sites need mobility to adopt an inhibitor-like conformation for proteolysis.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Serine proteinases are crucial enzymes involved in various biological processes.
- Serine proteinase inhibitors possess conserved recognition motifs for binding.
- Limited proteolytic sites on substrates have distinct conformations compared to inhibitors.
Purpose of the Study:
- To compare and contrast the molecular recognition of serine proteinase substrates and inhibitors.
- To investigate the conformational flexibility of limited proteolytic sites.
- To develop a predictive algorithm for identifying proteolytic sites.
Main Methods:
- Utilized coordinate sets from the Brookhaven Protein Databank for structural comparisons.
- Performed modeling experiments to assess the conformational adaptability of proteolytic sites.
- Analyzed conformational parameters including accessibility, protrusion, mobility, and secondary structure.
Main Results:
- In situ substrate conformations at limited proteolytic sites differ significantly from inhibitor-binding loops.
- Segmental mobility is proposed as a requirement for substrates to adopt an 'inhibitor-like' binding conformation.
- A predictive algorithm incorporating conformational parameters was developed.
Conclusions:
- Limited proteolytic sites likely require conformational changes to facilitate substrate binding and proteolysis.
- The developed algorithm can aid in predicting potential limited proteolytic sites within protein structures.
- Understanding these recognition mechanisms is key to enzyme function and inhibition studies.