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Alternative binding modes of an inhibitor to two different kinases.

De Moliner E, Brown NR, Johnson LN
Eur J Biochem 270 3174-81 (2003)
Cited: 37 times
EuropePMC logo PMID: 12869192

Abstract

Protein kinases are targets for therapeutic agents designed to intervene in signaling processes in the diseased state. Most kinase inhibitors are directed towards the conserved ATP binding site. Because the essential features of this site are conserved in all eukaryotic protein kinases, it is generally assumed that the same compound will bind in a similar manner to different protein kinases. The inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) is a selective inhibitor for the protein kinase CK2 (IC50 1.6 micro m) (Sarno et al. (2001) FEBS Letts.496, 44-48). Three other kinases [cyclin-dependent protein kinase 2 (CDK2), phosphorylase kinase and glycogen synthase kinase 3beta] exhibit approximately 10-fold weaker affinity for TBB than CK2. We report the crystal structure of TBB in complex with phospho-CDK2-cyclin A at 2.2 A resolution and compare the interactions with those observed for TBB bound to CK2. TBB binds at the ATP binding site of both kinases. In CDK2, each of the four bromine atoms makes polar contacts either to main chain oxygens in the hinge region of the kinase or to water molecules, in addition to several van der Waals contacts. The mode of binding of TBB to CDK2 is different from that to CK2. TBB in CDK2 is displaced more towards the hinge region between the N- and C-terminal lobes and rotated relative to TBB in CK2. The ATP binding pocket is wider in CDK2 than in CK2 resulting in fewer van der Waals contacts but TBB in CK2 does not contact the hinge. The structures show that, despite the conservation of the ATP binding pocket, the inhibitor is able to exploit different recognition features so that the same compound can bind in different ways to the two different kinases.

Reviews - 1p5e mentioned but not cited (1)

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Articles - 1p5e mentioned but not cited (3)

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Reviews citing this publication (4)

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  4. Doing more than just the structure-structural genomics in kinase drug discovery. Marsden BD, Knapp S. Curr Opin Chem Biol 12 40-45 (2008)

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  16. Prediction of specificity-determining residues for small-molecule kinase inhibitors. Caffrey DR, Lunney EA, Moshinsky DJ. BMC Bioinformatics 9 491 (2008)
  17. Structural basis for decreased affinity of Emodin binding to Val66-mutated human CK2 alpha as determined by molecular dynamics. Zhang N, Zhong R. J Mol Model 16 771-780 (2010)
  18. Halogen bonding at the ATP binding site of protein kinases: preferred geometry and topology of ligand binding. Poznański J, Shugar D. Biochim. Biophys. Acta 1834 1381-1386 (2013)
  19. Intermolecular charge flux as the origin of infrared intensity enhancement upon halogen-bond formation of the peptide group. Torii H. J Chem Phys 133 034504 (2010)
  20. Halogen Atoms in the Protein-Ligand System. Structural and Thermodynamic Studies of the Binding of Bromobenzotriazoles by the Catalytic Subunit of Human Protein Kinase CK2. Czapinska H, Winiewska-Szajewska M, Szymaniec-Rutkowska A, Piasecka A, Bochtler M, Poznański J. J Phys Chem B 125 2491-2503 (2021)
  21. The structure, properties, and nature of unconventional π halogen bond in the complexes of Al4(2-) and halohydrocarbons. Li R, Li Q, Cheng J, Li W. J Mol Model 18 2311-2319 (2012)
  22. A Theoretical Study of the Halogen Bond between Heteronuclear Halogen and Benzene. Luo J, Dai H, Zeng C, Wu D, Cao M. Molecules 27 8078 (2022)
  23. From a MMP2/CK2 multitarget approach to the identification of potent and selective MMP13 inhibitors. Pastor M, Zapico JM, Coderch C, Maslyk M, Panchuk R, de Pascual-Teresa B, Ramos A. Org. Biomol. Chem. 17 916-929 (2019)
  24. Investigation of the interaction modes between nonpolar organic pollutants with ionizable functional groups and natural organic matter via AuNP-based colorimetric assays. Niu H, Wang S, Tan Y, Cai Y. Chem. Commun. (Camb.) 51 17140-17143 (2015)
  25. Molecular docking studies of protein-nucleotide complexes using MOLSDOCK (mutually orthogonal Latin squares DOCK). Viji SN, Balaji N, Gautham N. J Mol Model 18 3705-3722 (2012)
  26. Synthesis of Novel Halogenated Heterocycles Based on o-Phenylenediamine and Their Interactions with the Catalytic Subunit of Protein Kinase CK2. Winiewska-Szajewska M, Maciejewska AM, Speina E, Poznański J, Paprocki D. Molecules 26 3163 (2021)
  27. Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T. Sci Adv 5 eaau9060 (2019)
  28. Competition between hydrogen and halogen bonding in the structures of 5,10-dihydroxy-5,10-dihydroboranthrenes. Durka K, Luliński S, Jarzembska KN, Smętek J, Serwatowski J, Woźniak K. Acta Crystallogr B Struct Sci Cryst Eng Mater 70 157-171 (2014)
  29. Halogen vs hydrogen bonding in thiazoline-2-thione stabilization with σ- and π-electron acceptors adducts: theoretical and experimental study. El-Sheshtawy HS, Salman HM, El-Kemary M. Spectrochim Acta A Mol Biomol Spectrosc 137 442-449 (2015)


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