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Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.

Kontopidis G, Andrews MJ, McInnes C, Cowan A, Powers H, Innes L, Plater A, Griffiths G, Paterson D, Zheleva DI, Lane DP, Green S, Walkinshaw MD, Fischer PM
Structure 11 1537-46 (2003)
Related entries: 1okv, 1ol1, 1ol2

Cited: 27 times
EuropePMC logo PMID: 14656438

Abstract

Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21(WAF1) and p27(KIP1) as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity. Here we present X-ray structures of the protein complex CDK2/CA, together with the cyclin groove-bound peptides H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH(2) (peptide 1), H-Arg-Arg-Leu-Ile-Phe-NH(2) (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH(2) (peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH(2) (peptide 4), and H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH(2) (peptide 5). Some of the peptide complexes presented here were obtained through the novel technique of ligand exchange within protein crystals. This method may find general application for obtaining complex structures of proteins with surface-bound ligands.

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  1. Preparing a database of corrected protein structures important in cell signaling pathways. Hatami S, Sirous H, Mahnam K, Najafipour A, Fassihi A. Res Pharm Sci 18 67-77 (2023)


Reviews citing this publication (4)

  1. Protein kinase inhibitors: contributions from structure to clinical compounds. Johnson LN. Q Rev Biophys 42 1-40 (2009)
  2. Drug discovery and mutant p53. Maslon MM, Hupp TR. Trends Cell Biol 20 542-555 (2010)
  3. Selectivity and potency of cyclin-dependent kinase inhibitors. Sridhar J, Akula N, Pattabiraman N. AAPS J 8 E204-21 (2006)
  4. ATP-noncompetitive inhibitors of CDK-cyclin complexes. Orzáez M, Gortat A, Mondragón L, Bachs O, Pérez-Payá E. ChemMedChem 4 19-24 (2009)

Articles citing this publication (22)

  1. REPLACE: a strategy for iterative design of cyclin-binding groove inhibitors. Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, Fischer PM. Chembiochem 7 1909-1915 (2006)
  2. Structural determinants of CDK4 inhibition and design of selective ATP competitive inhibitors. McInnes C, Wang S, Anderson S, O'Boyle J, Jackson W, Kontopidis G, Meades C, Mezna M, Thomas M, Wood G, Lane DP, Fischer PM. Chem Biol 11 525-534 (2004)
  3. Quantification of the effects of ionic strength, viscosity, and hydrophobicity on protein-ligand binding affinity. Papaneophytou CP, Grigoroudis AI, McInnes C, Kontopidis G. ACS Med Chem Lett 5 931-936 (2014)
  4. Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. Kontopidis G, McInnes C, Pandalaneni SR, McNae I, Gibson D, Mezna M, Thomas M, Wood G, Wang S, Walkinshaw MD, Fischer PM. Chem Biol 13 201-211 (2006)
  5. CDK2/cyclinA inhibitors: targeting the cyclinA recruitment site with small molecules derived from peptide leads. Castanedo G, Clark K, Wang S, Tsui V, Wong M, Nicholas J, Wickramasinghe D, Marsters JC, Sutherlin D. Bioorg Med Chem Lett 16 1716-1720 (2006)
  6. Proliferating cell nuclear antigen (PCNA) interactions in solution studied by NMR. De Biasio A, Campos-Olivas R, Sánchez R, López-Alonso JP, Pantoja-Uceda D, Merino N, Villate M, Martin-Garcia JM, Castillo F, Luque I, Blanco FJ. PLoS One 7 e48390 (2012)
  7. Optimization of non-ATP competitive CDK/cyclin groove inhibitors through REPLACE-mediated fragment assembly. Liu S, Premnath PN, Bolger JK, Perkins TL, Kirkland LO, Kontopidis G, McInnes C. J Med Chem 56 1573-1582 (2013)
  8. Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements. Liu S, Bolger JK, Kirkland LO, Premnath PN, McInnes C. ACS Chem Biol 5 1169-1182 (2010)
  9. An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data. Sugaya N, Ikeda K, Tashiro T, Takeda S, Otomo J, Ishida Y, Shiratori A, Toyoda A, Noguchi H, Takeda T, Kuhara S, Sakaki Y, Iwayanagi T. BMC Pharmacol 7 10 (2007)
  10. Truncation and optimisation of peptide inhibitors of cyclin-dependent kinase 2-cyclin a through structure-guided design. Kontopidis G, Andrews MJ, McInnes C, Plater A, Innes L, Renachowski S, Cowan A, Fischer PM. ChemMedChem 4 1120-1128 (2009)
  11. Iterative conversion of cyclin binding groove peptides into druglike CDK inhibitors with antitumor activity. Premnath PN, Craig SN, Liu S, Anderson EL, Grigoroudis AI, Kontopidis G, Perkins TL, Wyatt MD, Pittman DL, McInnes C. J Med Chem 58 433-442 (2015)
  12. Fragment based discovery of arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors. Premnath PN, Liu S, Perkins T, Abbott J, Anderson E, McInnes C. Bioorg Med Chem 22 616-622 (2014)
  13. Structural basis for the modulation of CDK-dependent/independent activity of cyclin D1. Ferrer JL, Dupuy J, Borel F, Jacquamet L, Noel JP, Dulic V. Cell Cycle 5 2760-2768 (2006)
  14. Protein conformational transitions coupled to binding in molecular recognition of unstructured proteins: hierarchy of structural loss from all-atom Monte Carlo simulations of p27Kip1 unfolding-unbinding and structural determinants of the binding mechanism. Verkhivker GM. Biopolymers 75 420-433 (2004)
  15. Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27(KIP1)-derived peptidomimetic inhibitors. Karthiga A, Tripathi SK, Shanmugam R, Suryanarayanan V, Singh SK. J Chem Biol 8 11-24 (2015)
  16. Bifunctional up-converting lanthanide nanoparticles for selective in vitro imaging and inhibition of cyclin D as anti-cancer agents. Chan CF, Tsang MK, Li H, Lan R, Chadbourne FL, Chan WL, Law GL, Cobb SL, Hao J, Wong WT, Wong KL. J Mater Chem B 2 84-91 (2014)
  17. Efficient soluble expression of active recombinant human cyclin A2 mediated by E. coli molecular chaperones. Grigoroudis AI, McInnes C, Premnath PN, Kontopidis G. Protein Expr Purif 113 8-16 (2015)
  18. Real time detection of cell cycle regulator cyclin A on living tumor cells with europium emission. Li H, Li H, Chadbourne FL, Lan R, Chan CF, Chan WL, Law GL, Lee CS, Cobb SL, Wong KL. Dalton Trans 42 13495-13501 (2013)
  19. Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy. Premnath PN, Craig SN, Liu S, McInnes C. Bioorg Med Chem Lett 26 3754-3760 (2016)
  20. Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors. Nandha Premnath P, Craig S, McInnes C. J Vis Exp e52441 (2015)
  21. Precipitant-ligand exchange technique reveals the ADP binding mode in Mycobacterium tuberculosis dethiobiotin synthetase. Thompson AP, Wegener KL, Booker GW, Polyak SW, Bruning JB. Acta Crystallogr D Struct Biol 74 965-972 (2018)
  22. Targeting Protein-Protein Interactions to Inhibit Cyclin-Dependent Kinases. Klein M. Pharmaceuticals (Basel) 16 519 (2023)


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