BÁRTOVÁ, Iveta, Michal OTYEPKA, Zdeněk KŘÍŽ and Jaroslav KOČA. A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION. In Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S. XIX. meeting of CSSBMB. Olomouc: Univerzita Palackého, 2004, p. 260-261. ISBN 80-244-0353-6.
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Basic information
Original name A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION
Name in Czech MD studie CDK2
Authors BÁRTOVÁ, Iveta (203 Czech Republic), Michal OTYEPKA (203 Czech Republic), Zdeněk KŘÍŽ (276 Germany) and Jaroslav KOČA (376 Israel, guarantor).
Edition XIX. meeting of CSSBMB. Olomouc, Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S, p. 260-261, 2 pp. 2004.
Publisher Univerzita Palackého
Other information
Original language English
Type of outcome Proceedings paper
Field of Study 10600 1.6 Biological sciences
Country of publisher Czech Republic
Confidentiality degree is not subject to a state or trade secret
RIV identification code RIV/00216224:14310/04:00010531
Organization unit Faculty of Science
ISBN 80-244-0353-6
Keywords in English cell cycle; CDK regulation; phosphorylated tyrosine; threonine
Tags CDK regulation, cell cycle, phosphorylated tyrosine, threonine
Changed by Changed by: prof. RNDr. Jaroslav Koča, DrSc., učo 610. Changed: 13/2/2005 16:42.
Abstract
The cyclin-dependent kinase-2, CDK2, controls the eukaryotic cell cycle at the G1 S boundary. CDK2 catalyzes the phosphoryl transfer of the adenosine-5-triphosphate (ATP) ?-phosphate to serine or threonine hydroxyl in the protein substrate. The CDK2 activity is regulated by complex mechanism including binding to positive regulatory subunit (Cyclin A or Cyclin E) and phosphorylation at positive regulatory site in the activation segment (T-loop) [1]. The CDK2 activity is inhibited in several ways, for example, by (de)phosphorylation, interaction with various artificial and natural protein inhibitors [2,3], etc. The CDK2 can be also negatively regulated by phosphorylation at Y15 and, to a lesser extent, at T14 residue in the inhibition segment (G-loop) [4]. Mechanism of the CDK2 inhibition by phosphorylation is known from the kinetics experiments but the structural aspects of inhibition remains unclear. The first attempt to explain the mechanism of inhibition by phosphorylation came from molecular dynamics simulations on the fully active CDK2 but without any peptide substrate [5]. This work broadens the previous study describing behavior of the fully active CDK2 (pT160-CDK2/Cyclin A/ATP complex) with bound the substrate peptide (HHASPRK) and CDK2 inhibited by phosphorylation at T14, Y15, and T14/Y15 residues in the G-loop using molecular dynamics simulations with the Cornell et al. force field as implemented in the AMBER 6.0 software package [6]. The inhibited complexes of CDK2 were prepared from X-ray structure of the pT160-CDK2/Cyclin A/HHASPRK/ATP complex (1QMZ PDB ID code) by in silico phosphorylation of the T14 and/or Y15 residues. Enzyme dynamics was studied during 15 ns long trajectory for the fully active CDK2 and 10 ns long trajectories for all inhibited CDK2. Differences in conformational behavior of key residues for substrate binding and phosphoryl transfer of fully active vs. inhibited CDK2 will be presented and compared to the previous work [5].
Abstract (in Czech)
MD studie CDK2
Links
MSM 143100005, plan (intention)Name: Strukturně-funkční vztahy biomolekul a jejich role v metabolismu
Investor: Ministry of Education, Youth and Sports of the CR, Biomolecular Structure-function Relationships and their role in the Metabolism
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