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

J 2005

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

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

Základní údaje

Originální název

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

Název česky

Mechanismus Aktivace a Inhibice CDK2

Autoři

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

Vydání

Protein Science, COLD SPRING HARBOR LAB PRESS, 2005, 0961-8368

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10403 Physical chemistry

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 3.618

Kód RIV

RIV/00216224:14310/05:00013624

Organizační jednotka

Přírodovědecká fakulta

UT WoS

000226626000019

Klíčová slova anglicky

cell cycle; CDK inhibition; phosphorylated tyrosine and threonine; glycine?rich loop; GxGxxG motif

Štítky

CDK inhibition, cell cycle, glycine?rich loop, GxGxxG motif, phosphorylated tyrosine and threonine

Změněno: 3. 6. 2005 17:11, prof. RNDr. Jaroslav Koča, DrSc.

Anotace

ORIG CZ

V originále

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). Tennanosecond- 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.

Česky

Aktivace a Inhibice CDK2

Návaznosti

MSM0021622413, záměr

Název: Proteiny v metabolismu a při interakci organismů s prostředím

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Proteiny v metabolismu a při interakci organismů s prostředím

Citovat

BÁRTOVÁ, Iveta; Michal OTYEPKA; Zdeněk KŘÍŽ a Jaroslav KOČA. 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. Protein Science. COLD SPRING HARBOR LAB PRESS, 2005, roč. 14, č. 2, s. 445-451. ISSN 0961-8368.

@article{567646,
   author = {Bártová, Iveta and Otyepka, Michal and Kříž, Zdeněk and Koča, Jaroslav},
   article_number = {2},
   keywords = {cell cycle; CDK inhibition; phosphorylated tyrosine and threonine; glycine?rich loop; GxGxxG motif},
   language = {eng},
   issn = {0961-8368},
   journal = {Protein Science},
   title = {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},
   volume = {14},
   year = {2005}
}

TY  - JOUR
ID  - 567646
AU  - Bártová, Iveta - Otyepka, Michal - Kříž, Zdeněk - Koča, Jaroslav
PY  - 2005
TI  - 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
JF  - Protein Science
VL  - 14
IS  - 2
SP  - 445-451
EP  - 445-451
PB  - COLD SPRING HARBOR LAB PRESS
SN  - 09618368
KW  - cell cycle
KW  - CDK inhibition
KW  - phosphorylated tyrosine and threonine
KW  - glycine?rich loop
KW  - GxGxxG motif
N2  - 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). Tennanosecond- 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.
ER  -

BÁRTOVÁ, Iveta; Michal OTYEPKA; Zdeněk KŘÍŽ a Jaroslav KOČA. 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. \textit{Protein Science}. COLD SPRING HARBOR LAB PRESS, 2005, roč.~14, č.~2, s.~445-451. ISSN~0961-8368.

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