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PDBsum entry 4iti

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4iti
Jmol
Contents
Protein chain
272 a.a.
Ligands
1HW ×2
PDB id:
4iti
Name: Transferase/transferase inhibitor
Title: Crystal structure of rip1 kinase in complex with necrostatin
Structure: Receptor-interacting serine/threonine-protein kin chain: a, b. Synonym: cell death protein rip, receptor-interacting prote 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:
2.86Å     R-factor:   0.229     R-free:   0.267
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q13546  (RIPK1_HUMAN) -  Receptor-interacting serine/threonine-protein kinase 1
Seq:
Struc:
 
Seq:
Struc:
671 a.a.
272 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    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.