PDBsum entry 2x1n

Cell cycle

PDB id: 2x1n

Contents

Protein chains

296 a.a. *

258 a.a. *

Ligands

ACE-LEU-ASN-PFF-NH2

X1N ×2

Waters ×86

* Residue conservation analysis

PDB id:

2x1n

Name:

Cell cycle

Title:

Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: cyclin-dependent kinase 2, p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: residues 172-432. Synonym: cyclin-a. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct.

Resolution:

2.75Å R-factor: 0.201 R-free: 0.255

Authors:

G.Kontopidis,M.J.Andrews,C.Mcinnes,A.Plater,L.Innes,S.Renachowski, A.Cowan,P.M.Fischer,N.A.Mcintyre,G.Griffiths,A.L.Barnett, A.M.Z.Slawin,W.Jackson,M.Thomas,D.I.Zheleva,S.Wang,D.G.Blake, N.J.Westwood

Key ref:

N.A.McIntyre et al. (2010). Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors. J Med Chem, 53, 2136-2145. PubMed id: 20146435

Date:

31-Dec-09 Release date: 16-Feb-10

Supersedes:

2wha

Protein chains

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

Seq: 298 a.a.

Struc: 296 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 258 a.a.

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

J Med Chem 53:2136-2145 (2010)

PubMed id: 20146435

Design, synthesis, and evaluation of 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as ring-constrained 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin-dependent kinase inhibitors.

N.A.McIntyre, C.McInnes, G.Griffiths, A.L.Barnett, G.Kontopidis, A.M.Slawin, W.Jackson, M.Thomas, D.I.Zheleva, S.Wang, D.G.Blake, N.J.Westwood, P.M.Fischer.

ABSTRACT

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K(i) values. The most potent compound reported in this study inhibits CDK2 with an IC(50) of 0.7 nM ([ATP] = 100 microM). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.