PDBsum entry 2rfd

Transferase

PDB id: 2rfd

Contents

Protein chains

288 a.a. *

16 a.a. *

15 a.a. *

Ligands

SO4

* Residue conservation analysis

PDB id:

2rfd

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. Mutation: yes. Erbb receptor feedback inhibitor 1. Chain: c, d. Fragment: sequence database residues, 340-364.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Organism_taxid: 9606

Resolution:

3.60Å R-factor: 0.234 R-free: 0.278

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

Date:

28-Sep-07 Release date: 04-Dec-07

Protein chains

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 288 a.a.*

Protein chain

Q9UJM3  (ERRFI_HUMAN) -  ERBB receptor feedback inhibitor 1 from Homo sapiens

Seq: 462 a.a.

Struc: 16 a.a.

Protein chain

Q9UJM3  (ERRFI_HUMAN) -  ERBB receptor feedback inhibitor 1 from Homo sapiens

Seq: 462 a.a.

Struc: 15 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

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.

ABSTRACT

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.