PDBsum entry 3dog

Transferase, cell cycle

PDB id: 3dog

Contents

Protein chains

298 a.a. *

262 a.a. *

268 a.a. *

Ligands

NNN ×2

SGM ×3

Waters ×215

* Residue conservation analysis

PDB id:

3dog

Name:

Transferase, cell cycle

Title:

Structure of thr 160 phosphorylated cdk2/cyclin a in complex with the inhibitor n-&-n1

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase, cdk2. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: unp residues 169-430. Synonym: cyclin-a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Bos taurus. Bovine, cow. Organism_taxid: 9913. Gene: ccna2, ccna.

Resolution:

2.70Å R-factor: 0.199 R-free: 0.248

Authors:

A.Echalier,J.Endicott

Key ref:

K.Bettayeb et al. (2008). N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine. Mol Cancer Ther, 7, 2713-2724. PubMed id: 18790752 DOI: 10.1158/1535-7163.MCT-08-0080

Date:

04-Jul-08 Release date: 30-Sep-08

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 298 a.a.*

Protein chains

P30274  (CCNA2_BOVIN) -  Cyclin-A2 from Bos taurus

Seq: 430 a.a.

Struc: 262 a.a.

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 268 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, C: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1158/1535-7163.MCT-08-0080

Mol Cancer Ther 7:2713-2724 (2008)

PubMed id: 18790752

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.

K.Bettayeb, H.Sallam, Y.Ferandin, F.Popowycz, G.Fournet, M.Hassan, A.Echalier, P.Bernard, J.Endicott, B.Joseph, L.Meijer.

ABSTRACT

Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.