Her2 activation mechanism reflects evolutionary preservation of asymmetric ectodomain dimers in the human EGFR family.
Elife
; 2: e00708, 2013 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-23878723
ABSTRACT
The receptor tyrosine kinase Her2, an intensely pursued drug target, differs from other members of the EGFR family in that it does not bind EGF-like ligands, relying instead on heterodimerization with other (ligand-bound) EGFR-family receptors for activation. The structural basis for Her2 heterodimerization, however, remains poorly understood. The unexpected recent finding of asymmetric ectodomain dimer structures of Drosophila EGFR (dEGFR) suggests a possible structural basis for Her2 heterodimerization, but all available structures for dimers of human EGFR family ectodomains are symmetric. Here, we report results from long-timescale molecular dynamics simulations indicating that a single ligand is necessary and sufficient to stabilize the ectodomain interface of Her2 heterodimers, which assume an asymmetric conformation similar to that of dEGFR dimers. This structural parallelism suggests a dimerization mechanism that has been conserved in the evolution of the EGFR family from Drosophila to human. DOIhttp//dx.doi.org/10.7554/eLife.00708.001.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Receptor ErbB-2
/
Receptores ErbB
Limite:
Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos