2YCF

Crystal Structure of Checkpoint Kinase 2 in complex with Inhibitor PV1531

Summary for 2YCF

• Entry DOI: 10.2210/pdb2ycf/pdb
• Related: 1GXC 2CN5 2CN8 2W0J 2W7X 2WTC 2WTD 2WTI 2WTJ 2XBJ 2XM8 2XM9
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK2, (2E)-N-hydroxy-2-[1-(4-{[(4-{(1E)-1-[2-(N'-hydroxycarbamimidoyl)hydrazinylidene]ethyl}phenyl)carbamoyl]amino}phenyl)ethylidene]hydrazinecarboximidamide, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: transferase, anticancer, anticancer drug design
• 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: 36959.89

Authors

Lountos, G.T.,Jobson, A.G.,Tropea, J.E.,Self, C.R.,Pommier, Y.,Shoemaker, R.H.,Zhang, G.,Waugh, D.S. (deposition date: 2011-03-14, release date: 2011-11-16, Last modification date: 2023-12-20)

Primary citation

Lountos, G.T.,Jobson, A.G.,Tropea, J.E.,Self, C.R.,Zhang, G.,Pommier, Y.,Shoemaker, R.H.,Waugh, D.S.
Structural Characterization of Inhibitor Complexes with Checkpoint Kinase 2 (Chk2), a Drug Target for Cancer Therapy.
J.Struct.Biol., 176:292-, 2011

PubMed Abstract: Chk2 (checkpoint kinase 2) is a serine/threonine kinase that participates in a series of signaling networks responsible for maintaining genomic integrity and responding to DNA damage. The development of selective Chk2 inhibitors has recently attracted much interest as a means of sensitizing cancer cells to current DNA-damaging agents used in the treatment of cancer. Additionally, selective Chk2 inhibitors may reduce p53-mediated apoptosis in normal tissues, thereby helping to mitigate adverse side effects from chemotherapy and radiation. Thus far, relatively few selective inhibitors of Chk2 have been described and none have yet progressed into clinical trials. Here, we report crystal structures of the catalytic domain of Chk2 in complex with a novel series of potent and selective small molecule inhibitors. These compounds exhibit nanomolar potencies and are selective for Chk2 over Chk1. The structures reported here elucidate the binding modes of these inhibitors to Chk2 and provide information that can be exploited for the structure-assisted design of novel chemotherapeutics.

PubMed: 21963792
DOI: 10.1016/J.JSB.2011.09.008

Experimental method

X-RAY DIFFRACTION (1.77 Å)