PDBsum entry 2rf9

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protein Protein-protein interface(s) links
Transferase PDB id
Protein chains
280 a.a. *
27 a.a. *
26 a.a. *
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of the complex between the egfr kinase domain and a mig6 peptide
Structure: Epidermal growth factor receptor. Chain: a, b. Fragment: protein kinase domain. Synonym: receptor tyrosine-protein kinase erbb-1. Engineered: yes. Erbb receptor feedback inhibitor 1. Chain: c, d. Fragment: sequence database residues, 315-374. Synonym: mitogen-inducible gene 6 protein, mig-6.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: errfi1, mig6. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
3.50Å     R-factor:   0.272     R-free:   0.329
Authors: X.Zhang,K.A.Pickin,R.Bose,N.Jura,P.A.Cole,J.Kuriyan
Key ref:
X.Zhang et al. (2007). Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature, 450, 741-744. PubMed id: 18046415 DOI: 10.1038/nature05998
28-Sep-07     Release date:   04-Dec-07    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor
1210 a.a.
280 a.a.
Protein chain
Pfam   ArchSchema ?
Q9UJM3  (ERRFI_HUMAN) -  ERBB receptor feedback inhibitor 1
462 a.a.
27 a.a.
Protein chain
Pfam   ArchSchema ?
Q9UJM3  (ERRFI_HUMAN) -  ERBB receptor feedback inhibitor 1
462 a.a.
26 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
+ [protein]-L-tyrosine
+ [protein]-L-tyrosine phosphate
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  


DOI no: 10.1038/nature05998 Nature 450:741-744 (2007)
PubMed id: 18046415  
Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface.
X.Zhang, K.A.Pickin, R.Bose, N.Jura, P.A.Cole, J.Kuriyan.
Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approximately 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.
  Selected figure(s)  
Figure 3.
Figure 3: Inhibition of EGFR kinase activity by MIG6(segments 1–2). a, Inhibition of the L834R mutant kinase in solution by peptides 336–412 or 336–412(Y358A) (containing both segment 1 and 2). The 30-residue peptide (containing segment 1 only) is used as a control. The insert shows an expanded view at low peptide concentrations. b, Inhibition of the wild-type kinase in solution by peptides 336–412 or 336–412(Y358A). Titration of peptide 336–412 beyond 30 M leads to unreliable results owing to precipitation of the protein and peptide (see Methods).
Figure 4.
Figure 4: A double-headed mechanism for EGFR inhibition by MIG6. a, A co-transfection experiment showing that EGFR(activator) can activate EGFR(activatable), and that MIG6 can inhibit this activation. b, Co-transfection experiments showing that full-length EGFR containing the L834R/V924R double mutation only shows autophosphorylation when co-transfected with EGFR(activator). Co-transfection combinations in a and b are represented by the cartoons in the respective lower panels, for clarity. The I682Q, D813N, L834R and V924R mutations are denoted in the cartoons by a circle, diamond, star and triangle, respectively. c, A schematic diagram showing the double-headed mechanism for EGFR inhibition by MIG6 involving both segment 1 and segment 2.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 450, 741-744) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22218287 N.J.Bessman, and M.A.Lemmon (2012).
Finding the missing links in EGFR.
  Nat Struct Mol Biol, 19, 1-3.  
21822280 L.Z.Mi, C.Lu, Z.Li, N.Nishida, T.Walz, and T.A.Springer (2011).
Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor.
  Nat Struct Mol Biol, 18, 984-989.  
20938978 M.Mustafa, A.Mirza, and N.Kannan (2011).
Conformational regulation of the EGFR kinase core by the juxtamembrane and C-terminal tail: a molecular dynamics study.
  Proteins, 79, 99.  
21474065 N.Jura, X.Zhang, N.F.Endres, M.A.Seeliger, T.Schindler, and J.Kuriyan (2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
  Mol Cell, 42, 9.  
21256157 R.Eglen, and T.Reisine (2011).
Drug discovery and the human kinome: recent trends.
  Pharmacol Ther, 130, 144-156.  
21333004 Y.Naruo, T.Nagashima, R.Ushikoshi-Nakayama, Y.Saeki, T.Nakakuki, T.Naka, H.Tanaka, S.F.Tsai, and M.Okada-Hatakeyama (2011).
Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity.
  BMC Syst Biol, 5, 29.  
22101934 Z.Wang, P.A.Longo, M.K.Tarrant, K.Kim, S.Head, D.J.Leahy, and P.A.Cole (2011).
Mechanistic insights into the activation of oncogenic forms of EGF receptor.
  Nat Struct Mol Biol, 18, 1388-1393.  
20946980 A.Bill, A.Schmitz, B.Albertoni, J.N.Song, L.C.Heukamp, D.Walrafen, F.Thorwirth, P.J.Verveer, S.Zimmer, L.Meffert, A.Schreiber, S.Chatterjee, R.K.Thomas, R.T.Ullrich, T.Lang, and M.Famulok (2010).
Cytohesins are cytoplasmic ErbB receptor activators.
  Cell, 143, 201-211.  
  21113414 C.G.Duncan, P.J.Killela, C.A.Payne, B.Lampson, W.C.Chen, J.Liu, D.Solomon, T.Waldman, A.J.Towers, S.G.Gregory, K.L.McDonald, R.E.McLendon, D.D.Bigner, and H.Yan (2010).
Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.
  Oncotarget, 1, 265-277.  
20723751 D.J.Leahy (2010).
The ins and outs of EGFR asymmetry.
  Cell, 142, 513-515.  
20351267 H.Ying, H.Zheng, K.Scott, R.Wiedemeyer, H.Yan, C.Lim, J.Huang, S.Dhakal, E.Ivanova, Y.Xiao, H.Zhang, J.Hu, J.M.Stommel, M.A.Lee, A.J.Chen, J.H.Paik, O.Segatto, C.Brennan, L.A.Elferink, Y.A.Wang, L.Chin, and R.A.DePinho (2010).
Mig-6 controls EGFR trafficking and suppresses gliomagenesis.
  Proc Natl Acad Sci U S A, 107, 6912-6917.  
20432069 J.H.Bae, and J.Schlessinger (2010).
Asymmetric tyrosine kinase arrangements in activation or autophosphorylation of receptor tyrosine kinases.
  Mol Cells, 29, 443-448.  
20022944 J.Monsey, W.Shen, P.Schlesinger, and R.Bose (2010).
Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system.
  J Biol Chem, 285, 7035-7044.  
20432460 K.Mahajan, and N.P.Mahajan (2010).
Shepherding AKT and androgen receptor by Ack1 tyrosine kinase.
  J Cell Physiol, 224, 327-333.  
20086093 Q.Lin, J.Wang, C.Childress, M.Sudol, D.J.Carey, and W.Yang (2010).
HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK.
  Mol Cell Biol, 30, 1541-1554.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
21085658 S.Tasaki, M.Nagasaki, H.Kozuka-Hata, K.Semba, N.Gotoh, S.Hattori, J.Inoue, T.Yamamoto, S.Miyano, S.Sugano, and M.Oyama (2010).
Phosphoproteomics-based modeling defines the regulatory mechanism underlying aberrant EGFR signaling.
  PLoS One, 5, e13926.  
20979614 V.Prieto-Echagüe, A.Gucwa, D.A.Brown, and W.T.Miller (2010).
Regulation of Ack1 localization and activity by the amino-terminal SAM domain.
  BMC Biochem, 11, 42.  
20421427 Y.Frosi, S.Anastasi, C.Ballarò, G.Varsano, L.Castellani, E.Maspero, S.Polo, S.Alemà, and O.Segatto (2010).
A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation.
  J Cell Biol, 189, 557-571.  
19236156 E.A.Hopper-Borge, R.E.Nasto, V.Ratushny, L.M.Weiner, E.A.Golemis, and I.Astsaturov (2009).
Mechanisms of tumor resistance to EGFR-targeted therapies.
  Expert Opin Ther Targets, 13, 339-362.  
19658168 E.Stuttfeld, and K.Ballmer-Hofer (2009).
Structure and function of VEGF receptors.
  IUBMB Life, 61, 915-922.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19815557 L.Pao-Chun, P.M.Chan, W.Chan, and E.Manser (2009).
Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling.
  J Biol Chem, 284, 34954-34963.  
18762271 N.Gotoh (2009).
Feedback inhibitors of the epidermal growth factor receptor signaling pathways.
  Int J Biochem Cell Biol, 41, 511-515.  
19563760 N.Jura, N.F.Endres, K.Engel, S.Deindl, R.Das, M.H.Lamers, D.E.Wemmer, X.Zhang, and J.Kuriyan (2009).
Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment.
  Cell, 137, 1293-1307.
PDB code: 3gt8
20007378 N.Jura, Y.Shan, X.Cao, D.E.Shaw, and J.Kuriyan (2009).
Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3.
  Proc Natl Acad Sci U S A, 106, 21608-21613.
PDB code: 3kex
19077689 P.A.Insel, and H.H.Patel (2009).
Membrane rafts and caveolae in cardiovascular signaling.
  Curr Opin Nephrol Hypertens, 18, 50-56.  
18761339 R.Bose, and X.Zhang (2009).
The ErbB kinase domain: structural perspectives into kinase activation and inhibition.
  Exp Cell Res, 315, 649-658.  
19762468 S.Mahapatra, H.Mehta, S.B.Woo, and K.E.Neet (2009).
Identification of critical residues within the conserved and specificity patches of nerve growth factor leading to survival or differentiation.
  J Biol Chem, 284, 33600-33613.  
19269802 T.Hunter (2009).
Tyrosine phosphorylation: thirty years and counting.
  Curr Opin Cell Biol, 21, 140-146.  
19674104 T.Nagashima, R.Ushikoshi-Nakayama, A.Suenaga, K.Ide, N.Yumoto, Y.Naruo, K.Takahashi, Y.Saeki, M.Taiji, H.Tanaka, S.F.Tsai, and M.Hatakeyama (2009).
Mutation of epidermal growth factor receptor is associated with MIG6 expression.
  FEBS J, 276, 5239-5251.  
18706412 W.H.Fry, L.Kotelawala, C.Sweeney, and K.L.Carraway (2009).
Mechanisms of ErbB receptor negative regulation and relevance in cancer.
  Exp Cell Res, 315, 697-706.  
18702810 C.Stortelers, R.Kerkhoven, and W.H.Moolenaar (2008).
Multiple actions of lysophosphatidic acid on fibroblasts revealed by transcriptional profiling.
  BMC Genomics, 9, 387.  
18602004 E.Petsalaki, and R.B.Russell (2008).
Peptide-mediated interactions in biological systems: new discoveries and applications.
  Curr Opin Biotechnol, 19, 344-350.  
18776048 U.Guha, R.Chaerkady, A.Marimuthu, A.S.Patterson, M.K.Kashyap, H.C.Harsha, M.Sato, J.S.Bader, A.E.Lash, J.D.Minna, A.Pandey, and H.E.Varmus (2008).
Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.
  Proc Natl Acad Sci U S A, 105, 14112-14117.  
18059449 D.J.Leahy (2007).
A monkey wrench in the kinase machine.
  Nat Struct Mol Biol, 14, 1120-1121.  
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.