PDBsum entry 3b2v

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protein ligands Protein-protein interface(s) links
Immune system/transferase PDB id
Protein chains
213 a.a. *
217 a.a. *
375 a.a. *
NAG ×2
* Residue conservation analysis
PDB id:
Name: Immune system/transferase
Title: Crystal structure of the extracellular region of the epiderm factor receptor in complex with the fab fragment of imc-11f
Structure: Imc-11f8 fab light chain. Chain: l. Engineered: yes. Imc-11f8 fab heavy chain. Chain: h. Engineered: yes. Epidermal growth factor receptor. Chain: a. Fragment: extracellular domain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expressed in: mus musculus. Expression_system_taxid: 10090. Gene: egfr, erbb1.
3.30Å     R-factor:   0.286     R-free:   0.367
Authors: K.M.Ferguson,S.Li,P.Kussie
Key ref:
S.Li et al. (2008). Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8. Structure, 16, 216-227. PubMed id: 18275813 DOI: 10.1016/j.str.2007.11.009
19-Oct-07     Release date:   19-Feb-08    
Go to PROCHECK summary

Protein chain
No UniProt id for this chain
Struc: 213 a.a.
Protein chain
Pfam   ArchSchema ?
Q6GMX6  (Q6GMX6_HUMAN) -  IGH@ protein
465 a.a.
217 a.a.*
Protein chain
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
1210 a.a.
375 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 16 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
Bound ligand (Het Group name = NAG)
matches with 47.62% similarity
+ [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  


DOI no: 10.1016/j.str.2007.11.009 Structure 16:216-227 (2008)
PubMed id: 18275813  
Structural basis for EGF receptor inhibition by the therapeutic antibody IMC-11F8.
S.Li, P.Kussie, K.M.Ferguson.
Therapeutic anticancer strategies that target and inactivate the epidermal growth factor receptor (EGFR) are under intense study in the clinic. Here we describe the mechanism of EGFR inhibition by an antibody drug IMC-11F8. IMC-11F8 is a fully human antibody that has similar antitumor potency as the chimeric cetuximab/Erbitux and might represent a safer therapeutic alternative. We report the X-ray crystal structure of the Fab fragment of IMC-11F8 (Fab11F8) in complex with the entire extracellular region and with isolated domain III of EGFR. We compare this to our previous study of the cetuximab/EGFR interaction. Fab11F8 interacts with a remarkably similar epitope, but through a completely different set of interactions. Both the similarities and differences in binding of these two antibodies have important implications for the development of inhibitors that could exploit this same mechanism of EGFR inhibition.
  Selected figure(s)  
Figure 4.
Figure 4. Features of the Shared Fab11F8, FabC225, and EGF Binding Region on Domain III
(A) Molecular surface representations of domain III of sEGFR with the contact regions (as defined in Figure 3D) colored red for Fab11F8, yellow for FabC225, and blue for EGF. Orientation is looking down onto the domain III binding site.
(B) Functional features of the domain III molecular surface. In the left panel, the surface is colored by atom type: negative, red; positive, blue; polar oxygen, pink; polar nitrogen, light blue; and apolar, white. The right panel shows the electrostatic potential from −2.5 kT (red) to +2.5 kT (blue) projected onto the surface. Electrostatic potential calculations used the adaptive Poisson-Boltzmann solver (APBS) implemented in PyMOL ([Baker et al., 2001] and [DeLano, 2004]).
(C) Orthogonal views of domain III. High-mannose chains (yellow) have been placed at each position of glycosylation on sEGFR guided by the one or two ordered sugar groups that are seen in the X-ray crystal structures. For reference, the contact region of Fab11F8 is shown (red).
(D) Three orientations of sEGFR are shown with the electrostatic potential, as in (B), projected on the surface and high-mannose chains shown. Both electrostatic and carbohydrate steering might play a role in guiding Fabs or ligands to the shared binding site on domain III.
Figure 8.
Figure 8. Mechanism of Inhibition of EGFR Activation by IMC-11F8 and by Cetuximab
(A) Cartoon model of Fab11F8 bound to sEGFR colored as in Figure 3A. Domain I and the N-terminal portion of domain II (gray) have been modeled using the coordinates from PDB ID code 1YY9.
(B) Cartoon of the FabC225/sEGFR complex (PDB ID code: 1YY9) colored as in (A).
(C) The mechanism of inhibition of ligand-induced dimerization and activation of EGFR for IMC-11F8 and cetuximab based on the structures presented here and in Li et al. (2005). The binding of the antibody to domain III of EGFR prevents ligand binding and might also sterically inhibit the conformational change that must occur for dimerization.
  The above figures are reprinted by permission from Cell Press: Structure (2008, 16, 216-227) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20017116 R.L.Rich, and D.G.Myszka (2010).
Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'.
  J Mol Recognit, 23, 1.  
19776018 I.C.Wilkinson, C.J.Hall, V.Veverka, J.Y.Shi, F.W.Muskett, P.E.Stephens, R.J.Taylor, A.J.Henry, and M.D.Carr (2009).
High resolution NMR-based model for the structure of a scFv-IL-1beta complex: potential for NMR as a key tool in therapeutic antibody design and development.
  J Biol Chem, 284, 31928-31935.
PDB code: 2kh2
18992239 K.R.Schmitz, and K.M.Ferguson (2009).
Interaction of antibodies with ErbB receptor extracellular regions.
  Exp Cell Res, 315, 659-670.  
19289842 T.P.Garrett, A.W.Burgess, H.K.Gan, R.B.Luwor, G.Cartwright, F.Walker, S.G.Orchard, A.H.Clayton, E.C.Nice, J.Rothacker, B.Catimel, W.K.Cavenee, L.J.Old, E.Stockert, G.Ritter, T.E.Adams, P.A.Hoyne, D.Wittrup, G.Chao, J.R.Cochran, C.Luo, M.Lou, T.Huyton, Y.Xu, W.D.Fairlie, S.Yao, A.M.Scott, and T.G.Johns (2009).
Antibodies specifically targeting a locally misfolded region of tumor associated EGFR.
  Proc Natl Acad Sci U S A, 106, 5082-5087.
PDB codes: 3g5v 3g5x 3g5y 3g5z
19258037 V.Ratushny, I.Astsaturov, B.A.Burtness, E.A.Golemis, and J.S.Silverman (2009).
Targeting EGFR resistance networks in head and neck cancer.
  Cell Signal, 21, 1255-1268.  
18394550 D.J.Leahy (2008).
A molecular view of anti-ErbB monoclonal antibody therapy.
  Cancer Cell, 13, 291-293.  
18585454 M.Peipp, M.Dechant, and T.Valerius (2008).
Effector mechanisms of therapeutic antibodies against ErbB receptors.
  Curr Opin Immunol, 20, 436-443.  
18606226 N.Lonberg (2008).
Fully human antibodies from transgenic mouse and phage display platforms.
  Curr Opin Immunol, 20, 450-459.  
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. Where a reference describes a PDB structure, the PDB code is shown on the right.