4ZJV

crystal structure of EGFR kinase domain in complex with Mitogen-inducible gene 6 protein

Summary for 4ZJV

• Entry DOI: 10.2210/pdb4zjv/pdb
• Related: 4R3P 4R3R
• Descriptor: Epidermal growth factor receptor, ERBB receptor feedback inhibitor 1 (3 entities in total)
• Functional Keywords: epidermal growth factor receptor (egfr), erbb receptor feedback inhibitor 1, mitogen-inducible gene 6 protein(mig6), transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533; Cytoplasm : Q9UJM3
• Total number of polymer chains: 4
• Total formula weight: 90880.29

Authors

Eck, M.J.,Park, E.,Lee, B. (deposition date: 2015-04-29, release date: 2015-08-12, Last modification date: 2024-11-20)

Primary citation

Park, E.,Kim, N.,Ficarro, S.B.,Zhang, Y.,Lee, B.I.,Cho, A.,Kim, K.,Park, A.K.,Park, W.Y.,Murray, B.,Meyerson, M.,Beroukhim, R.,Marto, J.A.,Cho, J.,Eck, M.J.
Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
Nat.Struct.Mol.Biol., 22:703-711, 2015

PubMed Abstract: Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectively targets activated receptors. Here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src. Crystal structures of human EGFR-Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and that can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1, the gene that encodes Mig6, in EGFR-amplified glioblastomas.

PubMed: 26280531
DOI: 10.1038/nsmb.3074

Experimental method

X-RAY DIFFRACTION (2.7 Å)