PDBsum entry 4itj

Transferase/transferase inhibitor

PDB id: 4itj

Contents

Protein chains

261 a.a.

276 a.a.

Ligands

1HX ×2

Metals

IOD ×9

Waters ×578

PDB id:

4itj

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of rip1 kinase in complex with necrostatin-4

Structure:

Receptor-interacting serine/threonine-protein kinase 1. Chain: a, b. Synonym: cell death protein rip, receptor-interacting protein 1, rip- 1, serine/threonine-protein kinase rip. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ripk1, rip, rip1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.80Å R-factor: 0.189 R-free: 0.222

Authors:

T.Xie,W.Peng,Y.Liu,C.Yan,Y.Shi

Key ref:

T.Xie et al. (2013). Structural basis of RIP1 inhibition by necrostatins. Structure, 21, 493-499. PubMed id: 23473668 DOI: 10.1016/j.str.2013.01.016

Date:

18-Jan-13 Release date: 13-Mar-13

Protein chain

Q13546  (RIPK1_HUMAN) -  Receptor-interacting serine/threonine-protein kinase 1 from Homo sapiens

Seq: 671 a.a.

Struc: 261 a.a.*

Protein chain

Q13546  (RIPK1_HUMAN) -  Receptor-interacting serine/threonine-protein kinase 1 from Homo sapiens

Seq: 671 a.a.

Struc: 276 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.str.2013.01.016

Structure 21:493-499 (2013)

PubMed id: 23473668

Structural basis of RIP1 inhibition by necrostatins.

T.Xie, W.Peng, Y.Liu, C.Yan, J.Maki, A.Degterev, J.Yuan, Y.Shi.

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.