Poly-L-proline type II peptide mimics as probes of the active site occupancy requirements of cGMP-dependent protein kinase

R. Zhang, C. K. Nicki, A. Marnai, S. Flemer, A. Natarajan, W. R. Dostmann, J. S. Madalengoitia

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Based on the X-ray crystal structure of cAMP-dependent protein kinase (PKA) with the endogenous inhibitor PKI and the X-ray crystal structure of cyclin-dependent kinase 2 (CDK2) with a substrate peptide, a proposal is put forth that some protein kinases bind peptide substrates in their active sites in the poly-L-proline type II (PPII) conformation. In this work, PPII peptide mimics are evaluated as pseudosubstrate inhibitors of cGMP-dependent protein kinase (PKG) to explore if PKG also binds peptide substrates in the PPII conformation. Inhibition data of our PPII mimetics provide evidence that the P - 1, P - 2, and P - 3 residues of substrate peptides bind in the PPII conformation (Φ approximately -75°, ψ approximately 145°). In addition, the inhibition data also suggest that the P - 1, P - 2, and P - 3 residues in substrate peptides bind with a gauche(-) χ1 angle. Copyright Blackwell Munksgaard, 2005.

Original languageEnglish (US)
Pages (from-to)151-159
Number of pages9
JournalJournal of Peptide Research
Volume66
Issue number4
DOIs
StatePublished - Oct 1 2005

Fingerprint

Cyclic GMP-Dependent Protein Kinases
Catalytic Domain
Peptides
Substrates
Conformations
Crystal structure
X-Rays
Cyclin-Dependent Kinase 2
X rays
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
polyproline

Keywords

  • PKG
  • Peptide mimics
  • Poly-L-proline
  • Protein kinase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Poly-L-proline type II peptide mimics as probes of the active site occupancy requirements of cGMP-dependent protein kinase. / Zhang, R.; Nicki, C. K.; Marnai, A.; Flemer, S.; Natarajan, A.; Dostmann, W. R.; Madalengoitia, J. S.

In: Journal of Peptide Research, Vol. 66, No. 4, 01.10.2005, p. 151-159.

Research output: Contribution to journalArticle

Zhang, R. ; Nicki, C. K. ; Marnai, A. ; Flemer, S. ; Natarajan, A. ; Dostmann, W. R. ; Madalengoitia, J. S. / Poly-L-proline type II peptide mimics as probes of the active site occupancy requirements of cGMP-dependent protein kinase. In: Journal of Peptide Research. 2005 ; Vol. 66, No. 4. pp. 151-159.
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AU - Flemer, S.

AU - Natarajan, A.

AU - Dostmann, W. R.

AU - Madalengoitia, J. S.

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AB - Based on the X-ray crystal structure of cAMP-dependent protein kinase (PKA) with the endogenous inhibitor PKI and the X-ray crystal structure of cyclin-dependent kinase 2 (CDK2) with a substrate peptide, a proposal is put forth that some protein kinases bind peptide substrates in their active sites in the poly-L-proline type II (PPII) conformation. In this work, PPII peptide mimics are evaluated as pseudosubstrate inhibitors of cGMP-dependent protein kinase (PKG) to explore if PKG also binds peptide substrates in the PPII conformation. Inhibition data of our PPII mimetics provide evidence that the P - 1, P - 2, and P - 3 residues of substrate peptides bind in the PPII conformation (Φ approximately -75°, ψ approximately 145°). In addition, the inhibition data also suggest that the P - 1, P - 2, and P - 3 residues in substrate peptides bind with a gauche(-) χ1 angle. Copyright Blackwell Munksgaard, 2005.

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