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PDBsum entry 4kro

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protein ligands Protein-protein interface(s) links
Transferase/immune system PDB id
4kro
Jmol
Contents
Protein chains
570 a.a.
116 a.a.
211 a.a.
213 a.a.
Ligands
NAG-NAG ×2
NAG ×3
Waters ×12
PDB id:
4kro
Name: Transferase/immune system
Title: Nanobody/vhh domain ega1 in complex with the extracellular r egfr
Structure: Epidermal growth factor receptor. Chain: a. Fragment: extracellular region (unp residues 25-642). Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein erbb-1. Engineered: yes. Nanobody/vhh domain ega1. Chain: b. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Lama glama. Llama. Organism_taxid: 9844.
Resolution:
3.05Å     R-factor:   0.224     R-free:   0.280
Authors: K.M.Ferguson,K.R.Schmitz
Key ref: K.R.Schmitz et al. (2013). Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains. Structure, 21, 1214-1224. PubMed id: 23791944 DOI: 10.1016/j.str.2013.05.008
Date:
16-May-13     Release date:   28-Aug-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
570 a.a.
Protein chain
No UniProt id for this chain
Struc: 116 a.a.
Protein chain
No UniProt id for this chain
Struc: 211 a.a.
Protein chain
No UniProt id for this chain
Struc: 213 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain A: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+
[protein]-L-tyrosine
Bound ligand (Het Group name = NAG)
matches with 47.62% similarity
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     ATP binding     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.str.2013.05.008 Structure 21:1214-1224 (2013)
PubMed id: 23791944  
 
 
Structural evaluation of EGFR inhibition mechanisms for nanobodies/VHH domains.
K.R.Schmitz, A.Bagchi, R.C.Roovers, P.M.van Bergen en Henegouwen, K.M.Ferguson.
 
  ABSTRACT  
 
The epidermal growth factor receptor (EGFR) is implicated in human cancers and is the target of several classes of therapeutic agents, including antibody-based drugs. Here, we describe X-ray crystal structures of the extracellular region of EGFR in complex with three inhibitory nanobodies, the variable domains of heavy chain only antibodies (VHH). VHH domains, the smallest natural antigen-binding modules, are readily engineered for diagnostic and therapeutic applications. All three VHH domains prevent ligand-induced EGFR activation, but use two distinct mechanisms. 7D12 sterically blocks ligand binding to EGFR in a manner similar to that of cetuximab. EgA1 and 9G8 bind an epitope near the EGFR domain II/III junction, preventing receptor conformational changes required for high-affinity ligand binding and dimerization. This epitope is accessible to the convex VHH paratope but inaccessible to the flatter paratope of monoclonal antibodies. Appreciating the modes of binding and inhibition of these VHH domains will aid in developing them for tumor imaging and/or cancer therapy.