Poly-L-proline type II peptide mimics as probes of the active site occupancy requirements of cGMP-dependent protein kinase.
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 (phi approximately -75 degrees, psi approximately 145 degrees). In addition, the inhibition data also suggest that the P-1, P-2, and P-3 residues in substrate peptides bind with a gauche(-) chi1 angle.
Zhang
R
R
Department of Chemistry, University of Vermont, Burlington, VT 05405, USA.
Nickl
C K
CK
Mamai
A
A
Flemer
S
S
Natarajan
A
A
Dostmann
W R
WR
Madalengoitia
J S
JS
D020134:Catalytic Domain / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D015335:Molecular Probes / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D015335:Molecular Probes; D010455:Peptides; C011083:polyproline; D017869:Cyclic GMP-Dependent Protein Kinases