title: Solution structure of the human Grb7-SH2 domain/erbB2 peptide complex and structural basis for Grb7 binding to ErbB2.
abstract: The solution structure of the hGrb7-SH2 domain in complex with a ten amino acid phosphorylated peptide ligand representative of the erbB2 receptor tyrosine kinase (pY1139) is presented as determined by nuclear magnetic resonance methods. The hGrb7-SH2 domain structure reveals the Src homology 2 domain topology consisting of a central beta-sheet capped at each end by an alpha-helix. The presence of a four residue insertion in the region between beta-strand E and the EF loop and resulting influences on the SH2 domain/peptide complex structure are discussed. The binding conformation of the erbB2 peptide is in a beta-turn similar to that found in phosphorylated tyrosine peptides bound to the Grb2-SH2 domain. To our knowledge this is only the second example of an SH2 domain binding its naturally occurring ligands in a turn, instead of extended, conformation. Close contacts between residues responsible for binding specificity in hGrb7-SH2 and the erbB2 peptide are characterized and the potential effect of mutation of these residues on the hGrb7-SH2 domain structure is discussed.
authors.affiliation: Department of Biochemistry, University of Vermont College of Medicine Burlington, VT 05405, U.S.A.
authors.forename: Monika
authors.initials: M
authors.lastname: Ivancic
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Lyons
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D001665:Binding Sites; D019281:Dimerization; D051382:GRB7 Adaptor Protein; D018734:Genes, erbB-2 / Q000502:physiology*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012996:Solutions; D013379:Substrate Specificity; D018909:src Homology Domains
chemical_list: D000596:Amino Acids; C495955:GRB7 protein, human; D008024:Ligands; D011506:Proteins; D012996:Solutions; D051382:GRB7 Adaptor Protein