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Related Experiment Videos

Conformational switching in an aspartic proteinase

A Y Lee1, S V Gulnik, J W Erickson

  • 1Structural Biochemistry Program, SAIC Frederick, National Cancer Institute, Maryland 21702-1201, USA.

Nature Structural Biology
|October 23, 1998
PubMed
Summary

The crystal structure of inactive Cathepsin D (CatDhi) reveals an N-terminal strand blocking the active site. This reversible structural change explains pH-dependent enzyme activity and substrate specificity.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Enzymology

Background:

  • Cathepsin D (CatD) is an aspartic proteinase involved in various cellular processes.
  • Understanding CatD's regulation is crucial for its role in physiology and disease.

Purpose of the Study:

  • To elucidate the structural basis of catalytically inactive Cathepsin D (CatDhi).
  • To investigate the mechanism of pH-dependent regulation of CatD activity and substrate specificity.

Main Methods:

  • X-ray crystallography was used to determine the structure of CatDhi at pH 7.5.
  • Structural analysis focused on the N-terminal region and active site cleft.

Main Results:

  • The crystal structure of CatDhi shows the N-terminal strand repositioned to block the active site cleft.
  • CatDhi shares structural similarity with Intermediate 3, a proposed transient form during enzyme activation.
  • A reversible interconversion between active and inactive CatD forms is suggested, regulated by an ionizable switch involving Glu 5, Glu 180, and Asp 187.

Conclusions:

  • The findings provide a structural explanation for the pH-dependent regulation of aspartic proteinase activity.
  • A novel mechanism for pH-dependent modulation of substrate specificity in CatD is proposed.

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