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PDBsum entry 2zpx

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protein Protein-protein interface(s) links
Cytokine PDB id
2zpx
Jmol
Contents
Protein chains
142 a.a. *
Waters ×7
* Residue conservation analysis
PDB id:
2zpx
Name: Cytokine
Title: Tnf receptor subtype one-selective tnf mutant with antagonistic activity; r1anttnf-t8
Structure: Tumor necrosis factor. Chain: a, b, c. Fragment: unp residues 77-233. Synonym: tnf-alpha, tumor necrosis factor ligand superfamily member 2, tnf-a, cachectin, antagonistic tnf mutant (r1anttnf-t8). Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Strain: human. Gene: tnf, tnfa, tnfsf2. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.83Å     R-factor:   0.268     R-free:   0.309
Authors: Y.Mukai,T.Nakamura,Y.Yamagata,Y.Tsutsumi
Key ref: Y.Mukai et al. (2009). Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists. J Biochem, 146, 167-172. PubMed id: 19386778
Date:
29-Jul-08     Release date:   24-Mar-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01375  (TNFA_HUMAN) -  Tumor necrosis factor
Seq:
Struc:
233 a.a.
142 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   1 term 
  Biochemical function     tumor necrosis factor receptor binding     1 term  

 

 
J Biochem 146:167-172 (2009)
PubMed id: 19386778  
 
 
Fast binding kinetics and conserved 3D structure underlie the antagonistic activity of mutant TNF: useful information for designing artificial proteo-antagonists.
Y.Mukai, T.Nakamura, Y.Yoshioka, H.Shibata, Y.Abe, T.Nomura, M.Taniai, T.Ohta, S.Nakagawa, S.Tsunoda, H.Kamada, Y.Yamagata, Y.Tsutsumi.
 
  ABSTRACT  
 
Tumour necrosis factor (TNF) is an important cytokine that induces an inflammatory response predominantly through the TNF receptor-1 (TNFR1). A crucial strategy for the treatment of many autoimmune diseases, therefore, is to block the binding of TNF to TNFR1. We previously identified a TNFR1-selective antagonistic mutant TNF (R1antTNF) from a phage library containing six randomized amino acid residues at the receptor-binding site (amino acids 84-89). Two R1antTNFs, R1antTNF-T2 (A84S, V85T, S86T, Y87H, Q88N and T89Q) and R1antTNF-T8 (A84T, V85P, S86A, Y87I, Q88N and T89R), were successfully isolated from this library. Here, we analysed R1antTNF-T8 using surface plasmon resonance spectroscopy and X-ray crystallography to determine the mechanism underlying the antagonistic activity of R1antTNF. The kinetic association/dissociation parameters of R1antTNF-T8 were higher than those of wild-type TNF, indicating more rapid bond dissociation. X-ray crystallographic analysis suggested that the binding mode of the T89R mutation changed from a hydrophobic to an electrostatic interaction, which may be responsible for the antagonistic behaviour of R1antTNF. Knowledge of these structure-function relationships will facilitate the design of novel TNF inhibitors based on the cytokine structure.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19837186 M.G.Tansey, and D.E.Szymkowski (2009).
The TNF superfamily in 2009: new pathways, new indications, and new drugs.
  Drug Discov Today, 14, 1082-1088.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.