Achieving Functionality Through Modular Build-up: Structure and Size Selection of Serine Oligopeptidases

Area of Science:

• Biochemistry
• Enzymology
• Structural Biology

Background:

• Prolyl oligopeptidase family enzymes (S9 family) are serine proteases with unique structural and regulatory features.
• They hydrolyze oligopeptides smaller than 30 amino acids and are implicated in amnesia, schizophrenia, type 2 diabetes, and other diseases.
• Understanding their substrate selectivity is crucial for drug development.

Purpose of the Study:

• To elucidate the structural basis of substrate selectivity and efficiency in the S9 enzyme family.
• To identify key structural features governing substrate size selection and enzyme regulation.
• To provide a framework for predicting the structure and function of uncharacterized S9 family members.

Main Methods:

• Comparative structural analysis of various S9 family enzyme members.
• Identification of conserved and variable structural elements.
• Correlation of structural features with substrate specificity and enzyme activity.

Main Results:

• Two critical structural features influencing selectivity and efficiency were identified: domain interaction stability and beta-edge accessibility.
• Domain interactions are crucial for stabilizing the catalytic triad, and their disruption can lead to enzyme deactivation.
• Beta-edge accessibility guides multimerization, forming channels for size-based substrate selection.

Conclusions:

• Structural insights into S9 family enzymes explain their unique substrate size selection mechanism.
• These findings offer a basis for designing novel inhibitors targeting S9 enzymes for therapeutic purposes.
• The identified structural cornerstones can predict the multimeric state and selection strategy of unknown S9 family structures.