4C8B

Structure of the kinase domain of human RIPK2 in complex with ponatinib

Summary for 4C8B

• Entry DOI: 10.2210/pdb4c8b/pdb
• Descriptor: RECEPTOR-INTERACTING SERINE/THREONINE-PROTEIN KINASE 2, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transferase, structural genomics
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : O43353
• Total number of polymer chains: 2
• Total formula weight: 77901.12

Authors

Canning, P.,Krojer, T.,Bradley, A.,Mahajan, P.,Goubin, S.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A. (deposition date: 2013-09-30, release date: 2013-10-16, Last modification date: 2023-12-20)

Primary citation

Canning, P.,Ruan, Q.,Schwerd, T.,Hrdinka, M.,Maki, J.L.,Saleh, D.,Suebsuwong, C.,Ray, S.,Brennan, P.E.,Cuny, G.D.,Uhlig, H.H.,Gyrd-Hansen, M.,Degterev, A.,Bullock, A.N.
Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors.
Chem. Biol., 22:1174-1184, 2015

PubMed Abstract: RIPK2 mediates pro-inflammatory signaling from the bacterial sensors NOD1 and NOD2, and is an emerging therapeutic target in autoimmune and inflammatory diseases. We observed that cellular RIPK2 can be potently inhibited by type II inhibitors that displace the kinase activation segment, whereas ATP-competitive type I inhibition was only poorly effective. The most potent RIPK2 inhibitors were the US Food and Drug Administration-approved drugs ponatinib and regorafenib. Their mechanism of action was independent of NOD2 interaction and involved loss of downstream kinase activation as evidenced by lack of RIPK2 autophosphorylation. Notably, these molecules also blocked RIPK2 ubiquitination and, consequently, inflammatory nuclear factor κB signaling. In monocytes, the inhibitors selectively blocked NOD-dependent tumor necrosis factor production without affecting lipopolysaccharide-dependent pathways. We also determined the first crystal structure of RIPK2 bound to ponatinib, and identified an allosteric site for inhibitor development. These results highlight the potential for type II inhibitors to treat indications of RIPK2 activation as well as inflammation-associated cancers.

PubMed: 26320862
DOI: 10.1016/j.chembiol.2015.07.017

Experimental method

X-RAY DIFFRACTION (2.75 Å)