PDBsum entry 5czi

Transferase

PDB id: 5czi

Contents

Protein chain

310 a.a.

Ligands

ASP-HIS-GLN-TYR-PTR-ASN-ASP

Waters ×129

PDB id:

5czi

Name:

Transferase

Title:

Egfr l858r mutant in complex with a shc peptide substrate

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: egfr unp residues 694-1022. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes. Shc peptide substrate. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Escherichia coli h489. Organism_taxid: 656404.

Resolution:

2.60Å R-factor: 0.185 R-free: 0.225

Authors:

C.H.Yun,M.J.Eck

Key ref:

M.J.Begley et al. (2015). EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src. Nat Struct Biol, 22, 983-990. PubMed id: 26551075 DOI: 10.1038/nsmb.3117

Date:

31-Jul-15 Release date: 30-Sep-15

Protein chain

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

Seq: 1210 a.a.

Struc: 310 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1038/nsmb.3117

Nat Struct Biol 22:983-990 (2015)

PubMed id: 26551075

EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.

M.J.Begley, C.H.Yun, C.A.Gewinner, J.M.Asara, J.L.Johnson, A.J.Coyle, M.J.Eck, I.Apostolou, L.C.Cantley.

ABSTRACT

Aberrant activation of the EGF receptor (EGFR) contributes to many human cancers by activating the Ras-MAPK pathway and other pathways. EGFR signaling is augmented by Src-family kinases, but the mechanism is poorly understood. Here, we show that human EGFR preferentially phosphorylates peptide substrates that are primed by a prior phosphorylation. Using peptides based on the sequence of the adaptor protein Shc1, we show that Src mediates the priming phosphorylation, thus promoting subsequent phosphorylation by EGFR. Importantly, the doubly phosphorylated Shc1 peptide binds more tightly than singly phosphorylated peptide to the Ras activator Grb2; this binding is a key step in activating the Ras-MAPK pathway. Finally, a crystal structure of EGFR in complex with a primed Shc1 peptide reveals the structural basis for EGFR substrate specificity. These results provide a molecular explanation for the integration of Src and EGFR signaling with downstream effectors such as Ras.