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Analogous inhibitors of elastase do not always bind analogously
C Mattos1, B Rasmussen, X Ding
1Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02254, USA.
Nature Structural Biology
|January 1, 1994
Summary
Enzyme active sites are more complex than previously assumed. New research on elastase reveals multiple binding modes and previously undiscovered subsites, challenging traditional methods for enzyme analysis.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Traditional enzyme studies assume a single binding site and mode for inhibitors.
- This assumption underlies structural and kinetic experiments used to define enzyme specificity.
- Elastase (a serine protease) has historically been studied under these assumptions.
Purpose of the Study:
- To investigate the binding modes of chemically similar inhibitors to elastase.
- To determine if elastase adheres to the traditional assumptions of enzyme-inhibitor interactions.
- To identify potential novel subsites within the elastase active site.
Main Methods:
- X-ray crystallography was used to determine the structures of three elastase-inhibitor complexes.
- Chemically similar inhibitors with comparable binding affinities were employed.
- Structural analysis focused on variations in inhibitor binding modes and interactions.
Main Results:
- Three distinct crystal structures revealed diverse binding modes for similar inhibitors.
- Two previously unidentified subsites on the elastase enzyme were discovered.
- Inhibitors with similar chemical properties and affinities exhibited different binding orientations.
Conclusions:
- The traditional assumptions regarding enzyme active sites do not apply to elastase.
- Elastase exhibits multiple binding sites and accommodates inhibitors in various modes.
- Researchers should exercise caution when using kinetic data to map enzyme subsites due to potential complexities.