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Crystal structure of papain-E64-c complex. Binding diversity of E64-c to papain S2 and S3 subsites
M J Kim1, D Yamamoto, K Matsumoto
1Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Japan.
The Biochemical Journal
|November 1, 1992
Summary
This study analyzed the atomic-level binding of E64-c inhibitor to papain using X-ray diffraction. Different binding modes were observed, both preventing solvent access to the active site.
Area of Science:
- Biochemistry
- Structural Biology
- Crystallography
Background:
- Papain is a cysteine proteinase with significant biological roles.
- Understanding enzyme-inhibitor interactions is crucial for drug development.
- E64-c is a synthetic inhibitor of cysteine proteinases.
Purpose of the Study:
- To determine the atomic-level binding mode of E64-c to papain.
- To compare different crystal forms of the E64-c-papain complex.
- To investigate the implications for substrate specificity.
Main Methods:
- X-ray diffraction analysis of the E64-c-papain complex at 1.9 A resolution.
- Molecular replacement for structure solution.
- Refinement of the complex structure.
- Calculation of accessible surface area.
- Molecular-dynamics simulations.
Main Results:
- The crystal structure of the E64-c-papain complex (Form II) was determined.
- Two distinct binding modes for E64-c were observed, differing in leucine and isoamylamide moieties.
- Both binding modes effectively blocked solvent access to the papain active site.
- Molecular dynamics simulations revealed two stationary states, one matching Form I and another differing from Form II.
Conclusions:
- The study provides atomic-level insights into E64-c inhibition of papain.
- Distinct binding modes influence inhibitor interaction with papain subsites.
- Results contribute to understanding papain substrate specificity.
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