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Mutations in B-type natriuretic peptide mediating receptor-A selectivity

J R Schoenfeld1, J Y Tom, D G Lowe

  • 1Department of Cardiovascular Research, Genentech, Inc., South San Francisco, CA 94080, USA.

FEBS Letters
|October 7, 1997
PubMed
Summary

Researchers engineered human B-type natriuretic peptide (hBNP) variants to improve binding to natriuretic peptide receptor-A (NPR-A) over natriuretic peptide receptor-C (NPR-C). A specific mutation (S19R) enhanced NPR-A selectivity 265-fold, offering insights into natriuretic peptide receptor interactions.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Natriuretic peptides are crucial regulators of cardiovascular homeostasis.
  • Selective targeting of natriuretic peptide receptors (NPRs) is a therapeutic goal.
  • Human B-type natriuretic peptide (hBNP) interacts with NPR-A and NPR-C.

Purpose of the Study:

  • To identify hBNP variants with enhanced binding affinity and selectivity for NPR-A over NPR-C.
  • To elucidate the structural determinants of hBNP receptor specificity.

Main Methods:

  • Construction and screening of monovalent display-phage libraries expressing mutant hBNP.
  • Characterization of receptor binding affinities using phage display technology.
  • Comparative analysis of hBNP and atrial natriuretic peptide (ANP) receptor interactions.

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Main Results:

  • Position 19 of hBNP was identified as a key determinant for receptor specificity.
  • The hBNP variant S19R exhibited a 265-fold improvement in NPR-A binding selectivity over NPR-C.
  • Mutations in the hBNP disulfide ring (G23F/L24W/G25R) yielded a 9-fold increase in selectivity.
  • Analogous mutations in ANP showed decreased NPR-A binding, indicating divergent recognition mechanisms.

Conclusions:

  • Specific mutations can significantly enhance hBNP selectivity for NPR-A.
  • The S19R mutation represents a promising variant for targeted NPR-A activation.
  • Differences in receptor recognition mechanisms exist between hBNP and ANP.