4A9R

CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR

4A9R の概要

• エントリーDOI: 10.2210/pdb4a9r/pdb
• 関連するPDBエントリー: 1GXC 2CN5 2CN8 2W0J 2W7X 2WTC 2WTD 2WTI 2WTJ 2XBJ 2XK9 2XM8 2XM9 2YCF 2YCQ 2YCR 2YCS 2YIQ 2YIR 2YIT 4A9S 4A9T 4A9U
• 分子名称: SERINE/THREONINE-PROTEIN KINASE CHK2, NITRATE ION, 2-[4-(4-CHLOROPHENOXY)PHENYL]-1H-BENZIMIDAZOLE-6-CARBOXAMIDE, ... (5 entities in total)
• 機能のキーワード: transferase, kinase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37599.71

構造登録者

Matijssen, C.,Silva-Santisteban, M.C.,Westwood, I.M.,Siddique, S.,Choi, V.,Sheldrake, P.,van Montfort, R.L.M.,Blagg, J. (登録日: 2011-11-28, 公開日: 2012-10-10, 最終更新日: 2023-12-20)

主引用文献

Matijssen, C.,Silva-Santisteban, M.C.,Westwood, I.M.,Siddique, S.,Choi, V.,Sheldrake, P.,Van Montfort, R.L.M.,Blagg, J.
Benzimidazole Inhibitors of the Protein Kinase Chk2: Clarification of the Binding Mode by Flexible Side Chain Docking and Protein-Ligand Crystallography
Bioorg.Med.Chem., 20:6630-, 2012

PubMed Abstract: Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature.

PubMed: 23058106
DOI: 10.1016/J.BMC.2012.09.024

実験手法

X-RAY DIFFRACTION (2.85 Å)