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Updated: May 15, 2026
08:59
Defining Substrate Specificities for Lipase and Phospholipase Candidates
Published on: November 23, 2016
Structural insights into aldosterone synthase substrate specificity and targeted inhibition
Natallia Strushkevich1, Andrei A Gilep, Limin Shen
1Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada M5G 1L7. natstrush@gmail.com
Molecular Endocrinology (Baltimore, Md.)
|January 17, 2013
Summary
Structural insights into aldosterone synthase reveal its catalytic mechanisms. Understanding these details aids in designing new drugs to treat hypertension by blocking excess aldosterone production.
Area of Science:
- Biochemistry
- Structural Biology
- Endocrinology
Background:
- Aldosterone regulates blood pressure and electrolyte balance.
- Dysregulated aldosterone is linked to hypertension and heart failure.
- Aldosterone synthase (CYP11B2) produces aldosterone.
Purpose of the Study:
- Determine the crystal structures of human aldosterone synthase.
- Elucidate the mechanism of aldosterone synthesis and inhibition.
- Provide a basis for designing novel antihypertensive agents.
Main Methods:
- X-ray crystallography of human aldosterone synthase.
- Complex structures with deoxycorticosterone (substrate) and fadrozole (inhibitor).
- Biochemical assays to assess enzyme activity.
Main Results:
- Revealed a hydrophobic cavity for corticosteroid recognition.
- Detailed substrate binding mode explaining 11β-hydroxylase activity.
- Identified key residues and structural features conferring 18-oxidase activity and isoform selectivity.
- Fadrozil binds in R-configuration, interacting with the egress channel.
Conclusions:
- Structural data provides insights into aldosterone synthase catalysis.
- Enables rational design of specific inhibitors for hypertension treatment.
- Understanding structural flexibility is key for isoform-selective inhibitor design.
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