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PDBsum entry 3c09

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protein ligands Protein-protein interface(s) links
Immune system/transferase PDB id
3c09
Jmol
Contents
Protein chains
211 a.a. *
216 a.a. *
191 a.a. *
175 a.a. *
191 a.a. *
Ligands
NAG ×10
BMA ×2
MAN
* Residue conservation analysis
PDB id:
3c09
Name: Immune system/transferase
Title: Crystal structure the fab fragment of matuzumab (fab72000) i with domain iii of the extracellular region of egfr
Structure: Matuzumab fab light chain. Chain: l, b. Engineered: yes. Other_details: human/mouse chimeric derivative of mouse mon antibody 425. Matuzumab fab heavy chain. Chain: h, c. Engineered: yes. Other_details: human/mouse chimeric derivative of mouse mon
Source: Homo sapiens, mus musculus. Human, house mouse. Organism_taxid: 9606,10090. Strain: ,. Expressed in: mus musculus. Expression_system_taxid: 10090. Expression_system_cell: mouse myeloma cell line. Homo sapiens. Human.
Resolution:
3.20Å     R-factor:   0.245     R-free:   0.299
Authors: K.M.Ferguson,J.Schmiedel,T.Knoechel
Key ref:
J.Schmiedel et al. (2008). Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell, 13, 365-373. PubMed id: 18394559 DOI: 10.1016/j.ccr.2008.02.019
Date:
18-Jan-08     Release date:   15-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
No UniProt id for this chain
Struc: 211 a.a.
Protein chain
No UniProt id for this chain
Struc: 216 a.a.
Protein chains
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1210 a.a.
191 a.a.*
Protein chain
No UniProt id for this chain
Struc: 175 a.a.
Protein chain
No UniProt id for this chain
Struc: 191 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, D: 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.ccr.2008.02.019 Cancer Cell 13:365-373 (2008)
PubMed id: 18394559  
 
 
Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization.
J.Schmiedel, A.Blaukat, S.Li, T.Knöchel, K.M.Ferguson.
 
  ABSTRACT  
 
An increasing number of therapeutic antibodies targeting tumors that express the epidermal growth factor receptor (EGFR) are in clinical use or late stages of clinical development. Here we investigate the molecular basis for inhibition of EGFR activation by the therapeutic antibody matuzumab (EMD72000). We describe the X-ray crystal structure of the Fab fragment of matuzumab (Fab72000) in complex with isolated domain III from the extracellular region of EGFR. Fab72000 interacts with an epitope on EGFR that is distinct from the ligand-binding region on domain III and from the cetuximab/Erbitux epitope. Matuzumab blocks ligand-induced receptor activation indirectly by sterically preventing the domain rearrangement and local conformational changes that must occur for high-affinity ligand binding and receptor dimerization.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. Implications for the Mechanism of Inhibition of EGFR by Matuzumab
(A) Cartoon of the extended sEGFR with Fab72000, in surface representation, docked onto its domain III epitope. The orientation of the receptor is the same as for the right-hand protomer in the sEGFR dimer shown in Figure 1 (with domains colored as for the left-hand protomer; EGF is omitted for clarity). The Fab72000 is colored as in Figure 3. The N-terminal region of domain I clashes with the V[L] domain (indicated with an arrow). Additional clashes occur along the C-terminal half of domain II (see [B]). The C-terminal loop on domain II (D278, H280) that makes critical contacts across the dimer interface is marked with an asterisk.
(B) In this view, an approximate 50° rotation about the vertical axis relative to (A), domain II is shown in sphere representation in dark green. A cartoon of domain II of the other molecule in the dimer is shown (light green) for reference. Domain I has been omitted for clarity. The V[L] domain of the Fab clashes with domain II in the critical C-terminal region that forms the binding pocket for the dimerization arm and makes important contacts with domain III (from N274 and E293 in domain II, colored orange). These interactions are known to be crucial for stabilizing the dimerization competent conformation of domain II. The Fab72000 epitope loop on domain III is colored in red.
Figure 7.
Figure 7. Matuzumab and Cetuximab Use Different Mechanisms to Block Ligand-Induced EGFR Dimerization and Activation
In the center of the scheme, the ligand-induced sEGFR dimer is represented, with domain I in red, domain II in green, domain III in gray with red border, domain IV in gray with green border, and the ligand (E) in violet. The colors for one protomer are lightened for contrast. On the left-hand side a scheme is shown to illustrate the mechanism of inhibition of ligand-induced dimerization by matuzumab. Fab72000 binds to domain III of sEGFR and sterically prevents the receptor from adopting the conformation required for dimerization. Importantly, Fab72000 blocks the local conformational changes in domain II that are critical for both high-affinity ligand binding and dimerization. The inhibition is noncompetitive; the ligand-binding site on domain III is not blocked. This contrasts with the mechanism of inhibition previously reported for cetuximab (Li et al., 2005). FabC225 (right side) is a competitive inhibitor that blocks the ligand-binding site on domain III. This is the primary mechanism of inhibition of ligand-mediated dimerization by cetuximab.
 
  The above figures are reprinted from an Open Access publication published by Cell Press: Cancer Cell (2008, 13, 365-373) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21443389 L.Hong, S.Li, Y.Han, J.Du, H.Zhang, J.Li, Q.Zhao, K.Wu, and D.Fan (2011).
Angiogenesis-related molecular targets in esophageal cancer.
  Expert Opin Investig Drugs, 20, 637-644.  
21498564 M.Muda, A.W.Gross, J.P.Dawson, C.He, E.Kurosawa, R.Schweickhardt, M.Dugas, M.Soloviev, A.Bernhardt, D.Fischer, J.S.Wesolowski, C.Kelton, B.Neuteboom, and B.Hock (2011).
Therapeutic assessment of SEED: a new engineered antibody platform designed to generate mono- and bispecific antibodies.
  Protein Eng Des Sel, 24, 447-454.  
20514015 C.Hartmann, N.Müller, A.Blaukat, J.Koch, I.Benhar, and W.S.Wels (2010).
Peptide mimotopes recognized by antibodies cetuximab and matuzumab induce a functionally equivalent anti-EGFR immune response.
  Oncogene, 29, 4517-4527.  
20739887 I.Vivanco, and I.K.Mellinghoff (2010).
Epidermal growth factor receptor inhibitors in oncology.
  Curr Opin Oncol, 22, 573-578.  
  20714355 M.A.Tejani, R.B.Cohen, and R.Mehra (2010).
The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer.
  Biologics, 4, 173-185.  
20021208 M.Hollmén, and K.Elenius (2010).
Potential of ErbB4 antibodies for cancer therapy.
  Future Oncol, 6, 37-53.  
20813958 P.Nagy, J.Claus, T.M.Jovin, and D.J.Arndt-Jovin (2010).
Distribution of resting and ligand-bound ErbB1 and ErbB2 receptor tyrosine kinases in living cells using number and brightness analysis.
  Proc Natl Acad Sci U S A, 107, 16524-16529.  
20357769 R.Diskin, P.M.Marcovecchio, and P.J.Bjorkman (2010).
Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity.
  Nat Struct Mol Biol, 17, 608-613.
PDB codes: 3lmj 3lqa
20157276 R.E.Gillilan, M.J.Cook, S.W.Cornaby, and D.H.Bilderback (2010).
Microcrystallography using single-bounce monocapillary optics.
  J Synchrotron Radiat, 17, 227-236.  
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.  
19159467 J.A.Katzel, M.P.Fanucchi, and Z.Li (2009).
Recent advances of novel targeted therapy in non-small cell lung cancer.
  J Hematol Oncol, 2, 2.  
18992239 K.R.Schmitz, and K.M.Ferguson (2009).
Interaction of antibodies with ErbB receptor extracellular regions.
  Exp Cell Res, 315, 659-670.  
  20068398 M.Peipp, M.Dechant, and T.Valerius (2009).
Sensitivity and resistance to EGF-R inhibitors: approaches to enhance the efficacy of EGF-R antibodies.
  MAbs, 1, 590-599.  
19415280 M.W.Saif, K.I.Syrigos, S.Hotchkiss, J.Shanley, J.Grasso, T.M.Ferencz, K.Syrigos, and M.M.Shah (2009).
Successful desensitization with cetuximab after an infusion reaction to panitumumab in patients with metastatic colorectal cancer.
  Cancer Chemother Pharmacol, 65, 107-112.  
19077689 P.A.Insel, and H.H.Patel (2009).
Membrane rafts and caveolae in cardiovascular signaling.
  Curr Opin Nephrol Hypertens, 18, 50-56.  
19552968 R.Jefferis (2009).
Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action.
  Trends Pharmacol Sci, 30, 356-362.  
19216848 S.C.Lee, A.López-Albaitero, and R.L.Ferris (2009).
Immunotherapy of head and neck cancer using tumor antigen-specific monoclonal antibodies.
  Curr Oncol Rep, 11, 156-162.  
19258452 S.Li, H.Wang, B.Peng, M.Zhang, D.Zhang, S.Hou, Y.Guo, and J.Ding (2009).
Efalizumab binding to the LFA-1 alphaL I domain blocks ICAM-1 binding via steric hindrance.
  Proc Natl Acad Sci U S A, 106, 4349-4354.
PDB codes: 3eo9 3eoa 3eob
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
18585454 M.Peipp, M.Dechant, and T.Valerius (2008).
Effector mechanisms of therapeutic antibodies against ErbB receptors.
  Curr Opin Immunol, 20, 436-443.  
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 codes are shown on the right.