2R3K

Crystal Structure of Cyclin-Dependent Kinase 2 with inhibitor

Summary for 2R3K

• Entry DOI: 10.2210/pdb2r3k/pdb
• Related: 2R3F 2R3G 2R3H 2R3I 2R3J 2R3L 2R3M 2R3N 2R3O 2R3P 2R3Q 2R3R
• Descriptor: Cell division protein kinase 2, 3-bromo-5-phenyl-N-(pyrimidin-5-ylmethyl)pyrazolo[1,5-a]pyridin-7-amine (3 entities in total)
• Functional Keywords: serine/threonine-protein kinase, cell cycle, inhibition, cyclin-dependent kinase, cancer, atp-binding, cell division, mitosis, nucleotide-binding, phosphorylation, polymorphism, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34414.77

Authors

Fischmann, T.O.,Hruza, A.W.,Madison, V.M.,Duca, J.S. (deposition date: 2007-08-29, release date: 2008-01-22, Last modification date: 2011-07-13)

Primary citation

Fischmann, T.O.,Hruza, A.,Duca, J.S.,Ramanathan, L.,Mayhood, T.,Windsor, W.T.,Le, H.V.,Guzi, T.J.,Dwyer, M.P.,Paruch, K.,Doll, R.J.,Lees, E.,Parry, D.,Seghezzi, W.,Madison, V.
Structure-guided discovery of cyclin-dependent kinase inhibitors.
Biopolymers, 89:372-379, 2008

PubMed 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.

PubMed: 17937404
DOI: 10.1002/bip.20868

Experimental method

X-RAY DIFFRACTION (1.7 Å)