4A9U

CRYSTAL STRUCTURE OF HUMAN CHK2 IN COMPLEX WITH BENZIMIDAZOLE CARBOXAMIDE INHIBITOR

Summary for 4A9U

• Entry DOI: 10.2210/pdb4a9u/pdb
• Related: 1GXC 2CN5 2CN8 2W0J 2W7X 2WTC 2WTD 2WTI 2WTJ 2XBJ 2XK9 2XM8 2XM9 2YCF 2YCQ 2YCR 2YCS 2YIQ 2YIR 2YIT 4A9R 4A9S 4A9T
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK2, NITRATE ION, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• Total number of polymer chains: 1
• Total formula weight: 38208.45

Authors

Matijssen, C.,Silva-Santisteban, M.C.,Westwood, I.M.,Siddique, S.,Choi, V.,Sheldrake, P.,van Montfort, R.L.M.,Blagg, J. (deposition date: 2011-11-28, release date: 2012-10-10, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.48 Å)