title: Diversity of bisubstrate binding modes of adenosine analogue-oligoarginine conjugates in protein kinase a and implications for protein substrate interactions.
abstract: Crystal structures of the catalytic subunit α of cAMP-dependent protein kinase (PKAc) with three adenosine analogue-oligoarginine conjugates (ARCs) are presented. The rationally designed ARCs include moieties that, in combination, target both the ATP- and the peptide-substrate-binding sites of PKAc, thereby taking advantage of high-affinity binding interactions offered by the ATP site while utilizing an additional mechanism for target specificity via binding to the peptide substrate site. The crystal structures demonstrate that, in accord with the previously reported bisubstrate character of ARCs, the inhibitors occupy both binding sites of PKAc. Further, they show new binding modes that may also apply to natural protein substrates of PKAc, which have not been revealed by previous crystallographic studies. The crystal structures described here contribute to the understanding of the substrate-binding patterns of PKAc and should also facilitate the design of inhibitors targeting PKAc and related protein kinases.
authors: Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway. Electronic address: alexander.pflug@uit.no.
authors: Alexander
authors: A
authors: Pflug
authors: Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia. Electronic address: rogozina@ut.ee.
authors: Jevgenia
authors: J
authors: Rogozina
authors: Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia. Electronic address: darjalav@ut.ee.
authors: Darja
authors: D
authors: Lavogina
authors: Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia. Electronic address: erki.enkvist@ut.ee.
authors: Erki
authors: E
authors: Enkvist
authors: Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia. Electronic address: asko.uri@ut.ee.
authors: Asko
authors: A
authors: Uri
authors: Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, N-9037 Tromsø, Norway. Electronic address: Richard.Engh@uit.no.
authors: Richard Alan
authors: RA
authors: Engh
authors: German Cancer Research Center, Group of Structural Biochemistry, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: d.bossemeyer@dkfz-heidelberg.de.
authors: Dirk
authors: D
authors: Bossemeyer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine