PDBsum entry 1m14

Transferase

PDB id: 1m14

Contents

Protein chain

307 a.a. *

Waters ×17

* Residue conservation analysis

PDB id:

1m14

Name:

Transferase

Title:

Tyrosine kinase domain from epidermal growth factor receptor

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: tyrosine kinase domain (residues 671-998). Synonym: receptor protein-tyrosine kinase erbb-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.60Å R-factor: 0.238 R-free: 0.286

Authors:

J.Stamos,M.X.Sliwkowski,C.Eigenbrot

Key ref:

J.Stamos et al. (2002). Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem, 277, 46265-46272. PubMed id: 12196540 DOI: 10.1074/jbc.M207135200

Date:

17-Jun-02 Release date: 04-Sep-02

Protein chain

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

Seq: 1210 a.a.

Struc: 307 a.a.

Enzyme reactions

• Enzyme class: 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: 10.1074/jbc.M207135200

J Biol Chem 277:46265-46272 (2002)

PubMed id: 12196540

Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor.

J.Stamos, M.X.Sliwkowski, C.Eigenbrot.

ABSTRACT

The crystal structure of the kinase domain from the epidermal growth factor receptor (EGFRK) including forty amino acids from the carboxyl-terminal tail has been determined to 2.6-A resolution, both with and without an EGFRK-specific inhibitor currently in Phase III clinical trials as an anti-cancer agent, erlotinib (OSI-774, CP-358,774, Tarceva(TM)). The EGFR family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains. Despite its lack of phosphorylation, we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor. Surprisingly, key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl-terminal substrate docking sites are found in close contact with the kinase domain. Significant intermolecular contacts involving the carboxyl-terminal tail are discussed with respect to receptor oligomerization.

Selected figure(s)

Figure 2.
Fig. 2. Activation loops. The close structural correspondence between the EGFRK A-loop (blue) and the A-loop from the phosphorylated form of the insulin receptor kinase (33) (gold) is shown. The hydrophobic interaction between Lys836 and Tyr845 almost exactly reprises that between Arg1155 and Tyr1163 of p-IRK (underlined). The presence of four glutamate residues in this part of EGFRK has been suggested as a cause for its intrinsic catalytic activity.

Figure 4.
Fig. 4. The LVI tripeptide segment of EGFRK is found in close association with the C-lobe. A solvent-accessible surface from EGFRK with LVI removed is depicted. Residue Leu955, the most important as gauged by mutagenesis studies, is found within what in its absence would be a hydrophobic pit.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 46265-46272) copyright 2002.

Figures were selected by the author.

Author's comment

It is very likely that the coordinate set in this entry chooses the wrong C-terminal as "belonging" to the rest of the polypeptide chain. Instead, a symmetry-related version that is described in the original Figure 5 is a more likely candidate.
The "LVI pocket" depicted in original Figure 4 is homologous to sites in Abl and Src kinases that are associated with allosteric control of kinase activity. See Hantschel et al. Cell. 2003 Mar 21;112(6):845-57, Nagar et al. Cell. 2003 Mar 21;112(6):859-71, and Cowan-Jacob et al. Structure. 2005 Jun;13(6):861-71.
A 2006 paper in Cell (Zhang et al. Cell. 2006 Jun 16;125(6):1137-49) expands on a crystal packing contact in this crystal structure to show how extracellular dimerization of EGFR probably transduces an allosteric influence to produce the "active" kinase conformation that is seen here. This is the first direct structural evidence of an initial intracellular event in signal transduction in a receptor tyrosine kinase.
Charles Eigenbrot