title: Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha.
abstract: We report the crystal structure, at 2.5 A resolution, of a truncated human EGFR ectodomain bound to TGFalpha. TGFalpha interacts with both L1 and L2 domains of EGFR, making many main chain contacts with L1 and interacting with L2 via key conserved residues. The results indicate how EGFR family members can bind a family of highly variable ligands. In the 2:2 TGFalpha:sEGFR501 complex, each ligand interacts with only one receptor molecule. There are two types of dimers in the asymmetric unit: a head-to-head dimer involving contacts between the L1 and L2 domains and a back-to-back dimer dominated by interactions between the CR1 domains of each receptor. Based on sequence conservation, buried surface area, and mutagenesis experiments, the back-to-back dimer is favored to be biologically relevant.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia. tgarrett@wehi.edu.au
authors.forename: Thomas P J
authors.initials: TP
authors.lastname: Garrett
authors.forename: Neil M
authors.initials: NM
authors.lastname: McKern
authors.forename: Meizhen
authors.initials: M
authors.lastname: Lou
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Elleman
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Adams
authors.forename: George O
authors.initials: GO
authors.lastname: Lovrecz
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.forename: Morry J
authors.initials: MJ
authors.lastname: Frenkel
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hoyne
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: Colin W
authors.initials: CW
authors.lastname: Ward
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D017124:Conserved Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D016211:Transforming Growth Factor alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004220:Disulfides; D008024:Ligands; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors