title: NMR study of the differential contributions of residues of transforming growth factor alpha to association with its receptor.
abstract: A heteronuclear NMR study of human transforming growth factor alpha (TGFalpha) in complex with the epidermal growth factor receptor extracellular domain (EGFR-ED) provided an effective method for delineating the relative contributions of the residues of the ligand to its affinity for the receptor. In conjunction with previously obtained mutagenesis data, these results indicate that while a large number of residues are involved in complex formation and make up the binding interface, a small subset contribute most of the binding energy. They also show that while the residues which contribute to receptor binding are localized on one face of the molecule, the specific residues that play the major role in the affinity of TGFalpha in the complex are in two distinct regions of TGFalpha. This suggests that two small functional epitopes each composed of two residues exist within a larger structural epitope presented on the binding face. These results give the most detailed picture to date of the receptor binding determinants and yield further insight into the formation of the ligand-receptor complex.
authors.affiliation: Protein Engineering Network of Centres of Excellence, 713 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: C
authors.initials: C
authors.lastname: McInnes
authors.forename: S
authors.initials: S
authors.lastname: Grothe
authors.forename: M
authors.initials: M
authors.lastname: O'Connor-McCourt
authors.forename: B D
authors.initials: BD
authors.lastname: Sykes
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000939:Epitopes / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D016211:Transforming Growth Factor alpha / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000939:Epitopes; D008024:Ligands; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors