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Diversity of bisubstrate binding modes of adenosine analogue-oligoarginine conjugates in protein kinase a and implications for protein substrate interactions.

Pflug A, Rogozina J, Lavogina D, Enkvist E, Uri A, Engh RA, Bossemeyer D
J Mol Biol 403 66-77 (2010)
Related entries: 3ag9, 3agm

Cited: 12 times
EuropePMC logo PMID: 20732331

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.

Articles - 3agl mentioned but not cited (1)

  1. Conformational transition paths harbor structures useful for aiding drug discovery and understanding enzymatic mechanisms in protein kinases. Wong CF. Protein Sci 25 192-203 (2016)


Articles citing this publication (11)

  1. Protein-induced long lifetime luminescence of nonmetal probes. Enkvist E, Vaasa A, Kasari M, Kriisa M, Ivan T, Ligi K, Raidaru G, Uri A. ACS Chem Biol 6 1052-1062 (2011)
  2. A subnanomolar fluorescent probe for protein kinase CK2 interaction studies. Enkvist E, Viht K, Bischoff N, Vahter J, Saaver S, Raidaru G, Issinger OG, Niefind K, Uri A. Org Biomol Chem 10 8645-8653 (2012)
  3. Design and characterization of a potent and selective dual ATP- and substrate-competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor. Stebbins JL, De SK, Pavlickova P, Chen V, Machleidt T, Chen LH, Kuntzen C, Kitada S, Karin M, Pellecchia M. J Med Chem 54 6206-6214 (2011)
  4. Selective bisubstrate inhibitors with sub-nanomolar affinity for protein kinase Pim-1. Ekambaram R, Enkvist E, Vaasa A, Kasari M, Raidaru G, Knapp S, Uri A. ChemMedChem 8 909-913 (2013)
  5. Exploration of 3-methylisoquinoline-4-carbonitriles as protein kinase A inhibitors of Plasmodium falciparum. Buskes MJ, Harvey KL, Prinz B, Crabb BS, Gilson PR, Wilson DJ, Abbott BM. Bioorg Med Chem 24 2389-2396 (2016)
  6. Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2. Vahter J, Viht K, Uri A, Enkvist E. Bioorg Med Chem 25 2277-2284 (2017)
  7. Co-crystal structures of the protein kinase haspin with bisubstrate inhibitors. Lavogina D, Kestav K, Chaikuad A, Heroven C, Knapp S, Uri A. Acta Crystallogr F Struct Biol Commun 72 339-345 (2016)
  8. Rational drug-design approach supported with thermodynamic studies - a peptide leader for the efficient bi-substrate inhibitor of protein kinase CK2. Winiewska-Szajewska M, Płonka D, Zhukov I, Poznański J. Sci Rep 9 11018 (2019)
  9. Chemical Modification of Phage-Displayed Helix-Loop-Helix Peptides to Construct Kinase-Focused Libraries. Fujiwara D, Mihara K, Takayama R, Nakamura Y, Ueda M, Tsumuraya T, Fujii I. Chembiochem 22 3406-3409 (2021)
  10. Competitive ligands facilitate dissociation of the complex of bifunctional inhibitor and protein kinase. Ivan T, Enkvist E, Sinijarv H, Uri A. Biophys Chem 228 17-24 (2017)
  11. Inhibition of CREB phosphorylation by conjugates of adenosine analogues and arginine-rich peptides, inhibitors of PKA catalytic subunit. Kriisa M, Sinijärv H, Vaasa A, Enkvist E, Kostenko S, Moens U, Uri A. Chembiochem 16 312-319 (2015)


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