A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2
(CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY
PHOSPHORYLATION

D 2004

A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION

BÁRTOVÁ, Iveta; Michal OTYEPKA; Zdeněk KŘÍŽ a Jaroslav KOČA

Základní údaje

Originální název

A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION

Název česky

MD studie CDK2

Autoři

BÁRTOVÁ, Iveta; Michal OTYEPKA; Zdeněk KŘÍŽ a Jaroslav KOČA

Vydání

XIX. meeting of CSSBMB. Olomouc, Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S, od s. 260-261, 2 s. 2004

Nakladatel

Univerzita Palackého

Další údaje

Jazyk

angličtina

Typ výsledku

Stať ve sborníku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Kód RIV

RIV/00216224:14310/04:00010531

Organizační jednotka

Přírodovědecká fakulta

ISBN

80-244-0353-6

Klíčová slova anglicky

cell cycle; CDK regulation; phosphorylated tyrosine; threonine

Štítky

CDK regulation, cell cycle, phosphorylated tyrosine, threonine

Změněno: 13. 2. 2005 16:42, prof. RNDr. Jaroslav Koča, DrSc.

Anotace

ORIG CZ

V originále

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].

Česky

MD studie CDK2

Návaznosti

MSM 143100005, záměr

Název: Strukturně-funkční vztahy biomolekul a jejich role v metabolismu

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Strukturně-funkční vztahy biomolekul a jejich role v metabolismu

Citovat

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 BY PHOSPHORYLATION. In Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S. XIX. meeting of CSSBMB. Olomouc: Univerzita Palackého, 2004, s. 260-261. ISBN 80-244-0353-6.

@inproceedings{561318,
   author = {Bártová, Iveta and Otyepka, Michal and Kříž, Zdeněk and Koča, Jaroslav},
   address = {Olomouc},
   booktitle = {Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S},
   edition = {XIX. meeting of CSSBMB},
   keywords = {cell cycle; CDK regulation; phosphorylated tyrosine; threonine},
   language = {eng},
   location = {Olomouc},
   isbn = {80-244-0353-6},
   pages = {260-261},
   publisher = {Univerzita Palackého},
   title = {A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION},
   year = {2004}
}

TY  - CONF
ID  - 561318
AU  - Bártová, Iveta - Otyepka, Michal - Kříž, Zdeněk - Koča, Jaroslav
PY  - 2004
TI  - A MOLECULAR DYNAMICS STUDY OF THE CYCLIN-DEPENDENT KINASE-2 (CDK2) WITH SUBSTRATE PEPTIDE (HHASPRK) INHIBITION BY PHOSPHORYLATION
PB  - Univerzita Palackého
CY  - Olomouc
SN  - 8024403536
KW  - cell cycle
KW  - CDK regulation
KW  - phosphorylated tyrosine
KW  - threonine
N2  - 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].
ER  -

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 BY PHOSPHORYLATION. In \textit{Acta Univ. Palacki. Olomouc., Fac. Rer. Nat., Chemica 43S}. XIX. meeting of CSSBMB. Olomouc: Univerzita Palackého, 2004, s.~260-261. ISBN~80-244-0353-6.

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