PDBsum entry 3f5x

Transferase/cell cycle

PDB id: 3f5x

Contents

Protein chains

297 a.a. *

256 a.a. *

Ligands

GOL ×2

EZV ×2

SO4

Waters ×68

* Residue conservation analysis

PDB id:

3f5x

Name:

Transferase/cell cycle

Title:

Cdk-2-cyclin complex with indazole inhibitor 9 bound at its active site

Structure:

Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: unp residues 177-432. Synonym: cyclin-a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ccna2, ccn1, ccna. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.40Å R-factor: 0.266 R-free: 0.283

Authors:

J.R.Kiefer,J.E.Day,N.L.Caspers,K.J.Mathis,K.K.Kretzmer,R.A.Weinberg, B.A.Reitz,R.A.Stegeman,J.I.Trujillo,W.Huang,A.Thorarensen,L.Xing, A.Wrightstone,L.Christine,R.Compton,X.Li

Key ref:

J.I.Trujillo et al. (2009). 2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor. Bioorg Med Chem Lett, 19, 908-911. PubMed id: 19097791

Date:

04-Nov-08 Release date: 03-Feb-09

Protein chains

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

Seq: 298 a.a.

Struc: 297 a.a.

Protein chains

P20248  (CCNA2_HUMAN) -  Cyclin-A2 from Homo sapiens

Seq: 432 a.a.

Struc: 256 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

Bioorg Med Chem Lett 19:908-911 (2009)

PubMed id: 19097791

2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor.

J.I.Trujillo, J.R.Kiefer, W.Huang, A.Thorarensen, L.Xing, N.L.Caspers, J.E.Day, K.J.Mathis, K.K.Kretzmer, B.A.Reitz, R.A.Weinberg, R.A.Stegeman, A.Wrightstone, L.Christine, R.Compton, X.Li.

ABSTRACT

The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).