Activation and Inhibition of Cyclin-Dependent Kinase-2 by
Phosphorylation; A Molecular Dynamics Study Reveals the
Functional Importance of the Glycine-Rich Loop

J 2004

Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop

BÁRTOVÁ, Iveta, Michal OTYEPKA, Zdeněk KŘÍŽ and Jaroslav KOČA

Basic information

Original name

Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop

Name in Czech

Aktivace a Inhibice CDK2

Authors

BÁRTOVÁ, Iveta (203 Czech Republic, guarantor), Michal OTYEPKA (203 Czech Republic), Zdeněk KŘÍŽ (203 Czech Republic) and Jaroslav KOČA (203 Czech Republic)

Edition

Protein Science, COLD SPRING HARBOR LAB PRESS, 2004, 0961-8368

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10403 Physical chemistry

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 4.116

RIV identification code

RIV/00216224:14310/04:00010530

Organization unit

Faculty of Science

UT WoS

000221630900002

Keywords in English

cell cycle; CDK regulation; phosphorylated tyrosine; threonine

Abstract

ORIG CZ

V originále

Nanoseconds long molecular dynamics (MD) trajectories of differently active complexes of human cyclin-dependent kinase 2 (inactive CDK2/ATP, semi-active CDK2/Cyclin A/ATP, fully-active pT160-CDK2/Cyclin A/ATP, inhibited pT14-; pY15-; and pT14,pY15,pT160-CDK2/Cyclin A/ATP) are compared. The MD simulations results of CDK2 inhibition by phosphorylation at T14 and/or Y15 sites provide insight into structural aspects of CDK2 deactivation. The inhibitory sites are localized in the glycine-rich loop (G-loop) positioned opposite the activation T-loop. Phosphorylation of T14 and both inhibitory sites T14 and Y15 together causes ATP misalignment for phosphorylation and G-loop conformational change. This conformational change leads to the opening of the CDK2 substrate binding box. The phosphorylated Y15 residue negatively affects substrate binding or its correct alignment for ATP terminal phospho-group transfer to the CDK2 substrate. The MD simulations of the CDK2 activation process provide results in agreement with previous X-ray data.

In Czech

Aktivace a Inhibice CDK2

Links

GV201/98/K041, research and development project

Name: HCILAB - Laboratoř interakcí člověka s počítačem

Investor: Czech Science Foundation, HCILAB - Human-Computer Interactions Laboratory

LN00A016, research and development project

Name: BIOMOLEKULÁRNÍ CENTRUM

Investor: Ministry of Education, Youth and Sports of the CR, Biomolecular Center

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

Citovat

BÁRTOVÁ, Iveta, Michal OTYEPKA, Zdeněk KŘÍŽ and Jaroslav KOČA. Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop. Protein Science. COLD SPRING HARBOR LAB PRESS, 2004, vol. 13, No 6, p. 1449-1457. ISSN 0961-8368.

@article{561317,
   author = {Bártová, Iveta and Otyepka, Michal and Kříž, Zdeněk and Koča, Jaroslav},
   article_number = {6},
   keywords = {cell cycle; CDK regulation; phosphorylated tyrosine; threonine},
   language = {eng},
   issn = {0961-8368},
   journal = {Protein Science},
   title = {Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop},
   volume = {13},
   year = {2004}
}

TY  - JOUR
ID  - 561317
AU  - Bártová, Iveta - Otyepka, Michal - Kříž, Zdeněk - Koča, Jaroslav
PY  - 2004
TI  - Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop
JF  - Protein Science
VL  - 13
IS  - 6
SP  - 1449-1457
EP  - 1449-1457
PB  - COLD SPRING HARBOR LAB PRESS
SN  - 09618368
KW  - cell cycle
KW  - CDK regulation
KW  - phosphorylated tyrosine
KW  - threonine
N2  - Nanoseconds long molecular dynamics (MD) trajectories of differently active complexes of human cyclin-dependent kinase 2 (inactive CDK2/ATP, semi-active CDK2/Cyclin A/ATP, fully-active pT160-CDK2/Cyclin A/ATP, inhibited pT14-; pY15-; and pT14,pY15,pT160-CDK2/Cyclin A/ATP) are compared. The MD simulations results of CDK2 inhibition by phosphorylation at T14 and/or Y15 sites provide insight into structural aspects of CDK2 deactivation. The inhibitory sites are localized in the glycine-rich loop (G-loop) positioned opposite the activation T-loop. Phosphorylation of T14 and both inhibitory sites T14 and Y15 together causes ATP misalignment for phosphorylation and G-loop conformational change. This conformational change leads to the opening of the CDK2 substrate binding box. The phosphorylated Y15 residue negatively affects substrate binding or its correct alignment for ATP terminal phospho-group transfer to the CDK2 substrate. The MD simulations of the CDK2 activation process provide results in agreement with previous X-ray data.
ER  -

BÁRTOVÁ, Iveta, Michal OTYEPKA, Zdeněk KŘÍŽ and Jaroslav KOČA. Activation and Inhibition of Cyclin-Dependent Kinase-2 by Phosphorylation; A Molecular Dynamics Study Reveals the Functional Importance of the Glycine-Rich Loop. \textit{Protein Science}. COLD SPRING HARBOR LAB PRESS, 2004, vol.~13, No~6, p.~1449-1457. ISSN~0961-8368.

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