4ITJ

Crystal structure of RIP1 kinase in complex with necrostatin-4

Summary for 4ITJ

• Entry DOI: 10.2210/pdb4itj/pdb
• Related: 4ITH 4ITI
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, N-[(1S)-1-(2-chloro-6-fluorophenyl)ethyl]-5-cyano-1-methyl-1H-pyrrole-2-carboxamide, IODIDE ION, ... (4 entities in total)
• Functional Keywords: alpha/beta, rip1 kinase, necroptosis, necrostatins, kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q13546
• Total number of polymer chains: 2
• Total formula weight: 68691.07

Authors

Xie, T.,Peng, W.,Liu, Y.,Yan, C.,Shi, Y. (deposition date: 2013-01-18, release date: 2013-03-13, Last modification date: 2023-09-20)

Primary citation

Xie, T.,Peng, W.,Liu, Y.,Yan, C.,Maki, J.,Degterev, A.,Yuan, J.,Shi, Y.
Structural Basis of RIP1 Inhibition by Necrostatins.
Structure, 21:493-499, 2013

PubMed Abstract: Necroptosis is a cellular mechanism that mediates necrotic cell death. The receptor-interacting serine/threonine protein kinase 1 (RIP1) is an essential upstream signaling molecule in tumor-necrosis-factor-α-induced necroptosis. Necrostatins, a series of small-molecule inhibitors, suppress necroptosis by specifically inhibiting RIP1 kinase activity. Both RIP1 structure and the mechanisms by which necrostatins inhibit RIP1 remain unknown. Here, we report the crystal structures of the RIP1 kinase domain individually bound to necrostatin-1 analog, necrostatin-3 analog, and necrostatin-4. Necrostatin, caged in a hydrophobic pocket between the N- and C-lobes of the kinase domain, stabilizes RIP1 in an inactive conformation through interactions with highly conserved amino acids in the activation loop and the surrounding structural elements. Structural comparison of RIP1 with the inhibitor-bound oncogenic kinase B-RAF reveals partially overlapping binding sites for necrostatin and for the anticancer compound PLX4032. Our study provides a structural basis for RIP1 inhibition by necrostatins and offers insights into potential structure-based drug design.

PubMed: 23473668
DOI: 10.1016/j.str.2013.01.016

Experimental method

X-RAY DIFFRACTION (1.8 Å)