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5CZH

EGFR L858R MUTANT IN COMPLEX WITH AN OPTIMAL PEPTIDE SUBSTRATE

Summary for 5CZH
Entry DOI10.2210/pdb5czh/pdb
Related5CZI
DescriptorEpidermal growth factor receptor, Peptide substrate (3 entities in total)
Functional Keywordsegfr, l858r, kinase, egf, transferase
Biological sourceHomo sapiens (Human)
More
Cellular locationCell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
Total number of polymer chains2
Total formula weight38928.61
Authors
Yun, C.H.,Eck, M.J. (deposition date: 2015-07-31, release date: 2015-09-30, Last modification date: 2024-11-13)
Primary citationBegley, M.J.,Yun, C.H.,Gewinner, C.A.,Asara, J.M.,Johnson, J.L.,Coyle, A.J.,Eck, M.J.,Apostolou, I.,Cantley, L.C.
EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.
Nat.Struct.Mol.Biol., 22:983-990, 2015
Cited by
PubMed 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.
PubMed: 26551075
DOI: 10.1038/nsmb.3117
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.8 Å)
Structure validation

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