2R3M

Crystal Structure of Cyclin-Dependent Kinase 2 with inhibitor

2R3M の概要

• エントリーDOI: 10.2210/pdb2r3m/pdb
• 関連するPDBエントリー: 2R3F 2R3G 2R3H 2R3I 2R3J 2R3K 2R3L 2R3N 2R3O 2R3P 2R3Q 2R3R
• 分子名称: Cell division protein kinase 2, N-((2-aminopyrimidin-5-yl)methyl)-5-(2,6-difluorophenyl)-3-ethylpyrazolo[1,5-a]pyrimidin-7-amine (3 entities in total)
• 機能のキーワード: serine/threonine-protein kinase, cell cycle, inhibition, cyclin-dependent kinase, cancer, atp-binding, cell division, mitosis, nucleotide-binding, phosphorylation, polymorphism, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34415.91

構造登録者

Fischmann, T.O.,Hruza, A.W.,Madison, V.M.,Duca, J.S. (登録日: 2007-08-29, 公開日: 2008-01-22, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)