3BHY

Crystal structure of human death associated protein kinase 3 (DAPK3) in complex with a beta-carboline ligand

3BHY の概要

• エントリーDOI: 10.2210/pdb3bhy/pdb
• 分子名称: Death-associated protein kinase 3, CHLORIDE ION, (4R)-7,8-dichloro-1',9-dimethyl-1-oxo-1,2,4,9-tetrahydrospiro[beta-carboline-3,4'-piperidine]-4-carbonitrile, ... (4 entities in total)
• 機能のキーワード: death associated kinase, dapk3, zip kinase, zipk, dap kinase 3, dap like kinase, dlk, structural genomics consortium, sgc, apoptosis, atp-binding, chromatin regulator, nucleotide-binding, nucleus, serine/threonine-protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus . Isoform 1: Nucleus . Isoform 2: Nucleus : O43293
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32957.84

構造登録者

Filippakopoulos, P.,Rellos, P.,Eswaran, J.,Fedorov, O.,Berridge, G.,Niesen, F.,Bracher, F.,Huber, K.,Pike, A.C.W.,Roos, A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Weigelt, J.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2007-11-29, 公開日: 2007-12-25, 最終更新日: 2023-08-30)

主引用文献

Huber, K.,Brault, L.,Fedorov, O.,Gasser, C.,Filippakopoulos, P.,Bullock, A.N.,Fabbro, D.,Trappe, J.,Schwaller, J.,Knapp, S.,Bracher, F.
7,8-dichloro-1-oxo-beta-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes.
J.Med.Chem., 55:403-413, 2012

PubMed Abstract: Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-β-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

PubMed: 22136433
DOI: 10.1021/jm201286z

実験手法

X-RAY DIFFRACTION (1.24 Å)