A Molecular Dynamics Study of the Cyclin-Dependent Kinase-2 (CDK2) with Substrate Peptide (HHASPRK), Inhibition of CDK2 by Phosphorylation

BÁRTOVÁ, Iveta, Michal OTYEPKA, Zdeněk KŘÍŽ a Jaroslav KOČA. A Molecular Dynamics Study of the Cyclin-Dependent Kinase-2 (CDK2) with Substrate Peptide (HHASPRK), Inhibition of CDK2 by Phosphorylation. In Materials in Structure Chemistry, Biology, Physics and Technology. Praha: Krystalografická společnost, 2004, s. 42-43. ISBN 1211 - 5894.

Základní údaje

• Originální název: A Molecular Dynamics Study of the Cyclin-Dependent Kinase-2 (CDK2) with Substrate Peptide (HHASPRK), Inhibition of CDK2 by Phosphorylation
• Název anglicky: A Molecular Dynamics Study of the Cyclin-Dependent Kinase-2 (CDK2) with Substrate Peptide (HHASPRK), Inhibition of CDK2 by Phosphorylation
• Autoři: BÁRTOVÁ, Iveta (203 Česká republika, garant), Michal OTYEPKA (203 Česká republika), Zdeněk KŘÍŽ (203 Česká republika) a Jaroslav KOČA (203 Česká republika).
• Vydání: Praha, Materials in Structure Chemistry, Biology, Physics and Technology, od s. 42-43, 2 s. 2004.
• Nakladatel: Krystalografická společnost

Další údaje

• Originální jazyk: čeština
• Typ výsledku: Stať ve sborníku
• Obor: 10403 Physical chemistry
• Stát vydavatele: Česká republika
• Utajení: není předmětem státního či obchodního tajemství
• WWW: URL
• Kód RIV: RIV/00216224:14310/04:00009964
• Organizační jednotka: Přírodovědecká fakulta
• ISBN: 1211 - 5894
• Klíčová slova anglicky: Cyclin dependent kinase; inhibition; phosphorylation; molecular dynamics
• Štítky: Cyclin dependent kinase, inhibition, molecular dynamics, phosphorylation

Anotace

The cyclin-dependent kinase, CDK2, regulates the eukaryotic cell cycle at the G1; S boundary. CDKs activity is regulated by complex mechanism including binding to positive regulatory subunit and phosphorylation at positive and/or negative regulatory sites [1]. For activation CDK2 requires binding to Cyclin A or Cyclin E. The CDK2 obtains full activity after phosphorylation of the threonine residue (T160) in the activation segment (T-loop) [2]. CDK2 catalyzes the phosphoryl transfer of the adenosine-5-triphosphate (ATP) g-phosphate to serine or threonine hydroxyl in the protein substrate. The CDKs activity is inhibited in several ways, for example, by (de)phosphorylation, interaction with various natural protein inhibitors [3,4], etc. The CDK2 can be negatively regulated by phosphorylation at Y15 and, to a lesser extent, at T14 in the glycine-rich loop (G-loop) [5]. This work describes behavior of the fully active CDK2 (pT160-CDK2/Cyclin A/ATP complex) with substrate peptide (HHASPRK) and CDK2 inhibited by phosphorylation at T14, Y15, and T14/Y15 residues altogether in the G-loop using molecular dynamics simulations with the Cornell et al. force field as implemented in the AMBER software package [6]. Inhibited complexes of CDK2 were prepared from pT160-CDK2/Cyclin A/HHASPRK/ATP (1QMZ PDB ID code) by phosphorylation of the T14 and/or Y15 residues. Enzyme dynamics was studied during 8 ns long trajectory. Differences in conformational behavior of key residues for substrate binding and phosphoryl transfer of fully active vs. inhibited CDK2 will be presented.

Anotace anglicky

The cyclin-dependent kinase, CDK2, regulates the eukaryotic cell cycle at the G1; S boundary. CDKs activity is regulated by complex mechanism including binding to positive regulatory subunit and phosphorylation at positive and/or negative regulatory sites [1]. For activation CDK2 requires binding to Cyclin A or Cyclin E. The CDK2 obtains full activity after phosphorylation of the threonine residue (T160) in the activation segment (T-loop) [2]. CDK2 catalyzes the phosphoryl transfer of the adenosine-5-triphosphate (ATP) g-phosphate to serine or threonine hydroxyl in the protein substrate. The CDKs activity is inhibited in several ways, for example, by (de)phosphorylation, interaction with various natural protein inhibitors [3,4], etc. The CDK2 can be negatively regulated by phosphorylation at Y15 and, to a lesser extent, at T14 in the glycine-rich loop (G-loop) [5]. This work describes behavior of the fully active CDK2 (pT160-CDK2/Cyclin A/ATP complex) with substrate peptide (HHASPRK) and CDK2 inhibited by phosphorylation at T14, Y15, and T14/Y15 residues altogether in the G-loop using molecular dynamics simulations with the Cornell et al. force field as implemented in the AMBER software package [6]. Inhibited complexes of CDK2 were prepared from pT160-CDK2/Cyclin A/HHASPRK/ATP (1QMZ PDB ID code) by phosphorylation of the T14 and/or Y15 residues. Enzyme dynamics was studied during 8 ns long trajectory. Differences in conformational behavior of key residues for substrate binding and phosphoryl transfer of fully active vs. inhibited CDK2 will be presented.

Návaznosti

• LN00A016, projekt VaV: Název: BIOMOLEKULÁRNÍ CENTRUM

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Biomolekulární centrum