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The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed by the molecular dynamics study on the complex CDK2 with the peptide substrate HHASPRK

Iveta Bártová¹, Michal Otyepka^2,3, Zdenk K͹ and Jaroslav Koa¹

¹ National Centre for Biomolecular Research, Faculty of Science, Masaryk University, 611 37 Brno, Czech Republic
² Department of Physical Chemistry, Palacky University, 771 46 Olomouc, Czech Republic
³ Laboratory of Growth Regulators, Palacky University and Institute of Experimental Botany AS CR, 783 71 Olomouc, Czech Republic

(RECEIVED June 29, 2004; FINAL REVISION October 13, 2004; ACCEPTED October 18, 2004)

Molecular dynamics (MD) simulations were used to explain structural details of cyclin-dependent kinase-2 (CDK2) inhibition by phosphorylation at T14 and/or Y15 located in the glycine-rich loop (G-loop). Ten-nanosecond-long simulations of fully active CDK2 in a complex with a short peptide (HHASPRK) substrate and of CDK2 inhibited by phosphorylation of T14 and/or Y15 were produced. The inhibitory phosphorylations at T14 and/or Y15 show namely an ATP misalignment and a G-loop shift (~5 Å) causing the opening of the substrate binding box. The biological functions of the G-loop and GxGxxG motif evolutionary conservation in protein kinases are discussed. The position of the ATP -phosphate relative to the phosphorylation site (S/T) of the peptide substrate in the active CDK2 is described and compared with inhibited forms of CDK2. The MD results clearly provide an explanation previously not known as to why a basic residue (R/K) is preferred at the P₂ position in phosphorylated S/T peptide substrates.

Keywords: cell cycle; CDK inhibition; phosphorylated tyrosine and threonine; glycine-rich loop; GxGxxG motif

Abbreviations: p denotes phosphorylation, i.e., pT160 is phosphothreonine 160 • G-loop, glycine-rich loop (CDK2 residues 11–) • JST, pT160-CDK2/Cyclin A/ATP • QMZ, pT160-CDK2/Cyclin A/HHASPRK/ATP • pT14-QMZ, pT14,pT160-CDK2/Cyclin A/HHASPRK/ATP • pY15-QMZ, pY15,pT160-CDK2/Cyclin A/HHASPRK/ATP • pT14,pY15-QMZ, pT14, pY15,pT160-CDK2/Cyclin A/HHASPRK/ATP

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04959705.

Reprint requests to: Michal Otyepka, Department of Physical Chemistry, Palacky University, tr. Svobody 26, 771 46 Olomouc, Czech Republic; e-mail: otyepka{at}aix.upol.cz; fax: +420 585634425; or Jaroslav Koc a, National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic; e-mail: jkoca{at}chemi.muni.cz; fax +420 549492556.

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