6FU5

Structure of the kinase domain of human RIPK2 in complex with the inhibitor CSLP18

Summary for 6FU5

• Entry DOI: 10.2210/pdb6fu5/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 2, ~{N}-[5-[2-azanyl-5-(4-piperazin-1-ylphenyl)pyridin-3-yl]-2-methoxy-phenyl]propane-1-sulfonamide (3 entities in total)
• Functional Keywords: transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73734.92

Authors

Pinkas, D.M.,Bufton, J.C.,Kupinska, K.,Burgess-Brown, N.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Bullock, A.N. (deposition date: 2018-02-26, release date: 2018-04-25, Last modification date: 2024-01-17)

Primary citation

Hrdinka, M.,Schlicher, L.,Dai, B.,Pinkas, D.M.,Bufton, J.C.,Picaud, S.,Ward, J.A.,Rogers, C.,Suebsuwong, C.,Nikhar, S.,Cuny, G.D.,Huber, K.V.,Filippakopoulos, P.,Bullock, A.N.,Degterev, A.,Gyrd-Hansen, M.
Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling.
EMBO J., 37:-, 2018

PubMed Abstract: RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD-mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP pocket-binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and NOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling.

PubMed: 30026309
DOI: 10.15252/embj.201899372

Experimental method

X-RAY DIFFRACTION (3.26 Å)