PDBsum entry 2r3h

Transferase

PDB id: 2r3h

Contents

Protein chain

292 a.a. *

Ligands

SCE

Waters ×207

* Residue conservation analysis

PDB id:

2r3h

Name:

Transferase

Title:

Crystal structure of cyclin-dependent kinase 2 with inhibitor

Structure:

Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

1.50Å R-factor: 0.196 R-free: 0.219

Authors:

T.O.Fischmann,A.W.Hruza,V.M.Madison,J.S.Duca

Key ref:

T.O.Fischmann et al. (2008). Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers, 89, 372-379. PubMed id: 17937404 DOI: 10.1002/bip.20868

Date:

29-Aug-07 Release date: 22-Jan-08

Protein chain

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

Seq: 298 a.a.

Struc: 291 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1002/bip.20868

Biopolymers 89:372-379 (2008)

PubMed id: 17937404

Structure-guided discovery of cyclin-dependent kinase inhibitors.

T.O.Fischmann, A.Hruza, J.S.Duca, L.Ramanathan, T.Mayhood, W.T.Windsor, H.V.Le, T.J.Guzi, M.P.Dwyer, K.Paruch, R.J.Doll, E.Lees, D.Parry, W.Seghezzi, V.Madison.

ABSTRACT

CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity.