title: Poly-L-proline type II peptide mimics as probes of the active site occupancy requirements of cGMP-dependent protein kinase.
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 (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.
authors.affiliation: Department of Chemistry, University of Vermont, Burlington, VT 05405, USA.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: C K
authors.initials: CK
authors.lastname: Nickl
authors.forename: A
authors.initials: A
authors.lastname: Mamai
authors.forename: S
authors.initials: S
authors.lastname: Flemer
authors.forename: A
authors.initials: A
authors.lastname: Natarajan
authors.forename: W R
authors.initials: WR
authors.lastname: Dostmann
authors.forename: J S
authors.initials: JS
authors.lastname: Madalengoitia
mesh_terms: 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
chemical_list: D015335:Molecular Probes; D010455:Peptides; C011083:polyproline; D017869:Cyclic GMP-Dependent Protein Kinases