Related Experiment Videos
Inhibitor binding induces structural changes in porcine pepsin.
C Abad-Zapatero1, T J Rydel, D J Neidhart
1Laboratory of Protein Crystallography, Abbott Laboratories, Abbott Park, Illinois 60064.
Advances in Experimental Medicine and Biology
|January 1, 1991
Summary
Aspartic proteinases, like pepsin, undergo significant structural changes when inhibitors bind. These conformational shifts involve rigid body movements of residue clusters, impacting enzyme function.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Aspartic proteinases are a class of enzymes crucial in various biological processes.
- Understanding their structure-function relationship is key to drug development.
- Pepsin is a well-studied mammalian aspartic proteinase.
Purpose of the Study:
- To investigate conformational changes in pepsin upon inhibitor binding.
- To elucidate the structural basis of ligand-induced plasticity in aspartic proteinases.
Main Methods:
- X-ray crystallography was used to determine the refined structures of two isomorphous pepsin/inhibitor complexes.
- Analysis of conformational differences between the apo and holoenzyme states.
Main Results:
- Significant conformational changes were observed in pepsin upon inhibitor binding.
- These changes are primarily due to concerted rigid body movements of two distinct residue clusters relative to a central core.
- One cluster involves the flap, beta strand (sheet IV), helices, and loops in the amino domain.
- The other, larger cluster is located in the carboxy end, corresponding to a previously described flexible subdomain.
Conclusions:
- Ligand binding induces substantial conformational plasticity in mammalian aspartic proteinases.
- Similar conformational changes are likely to occur in related enzymes such as renin and cathepsin D.
- The identified structural rearrangements provide insights into the mechanism of action and inhibition of aspartic proteinases.