Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands.
Two dodecapeptides belonging to distinct classes of Src homology 3 (SH3) ligands and selected from biased phage display libraries were used to investigate interactions between a specificity pocket in the Src SH3 domain and ligant residues flanking the proline-rich core. The solution structures of c-Src SH3 complexed with these peptides were solved by NMR. In addition to proline-rich, polyproline type II helix-forming core, the class I and II ligands each possesses a flanking sequence that occupies a large pocket between the RT and n-Src loops of the SH3 domain. Structural and mutational analyses illustrate how the two classes of SH3 ligands exploit a specificity pocket on the receptor differently to increase binding affinity and specificity.
Feng
S
S
Howard Hughes Medical Institute, Department of Chemistry, Harvard University, Cambridge, MA 02138, USA.
Kasahara
C
C
Rickles
R J
RJ
Schreiber
S L
SL
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009842:Oligopeptides / Q000737:chemistry; D011392:Proline; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008024:Ligands; D009842:Oligopeptides; D011506:Proteins; D011994:Recombinant Proteins; D011392:Proline; D011494:Protein Kinases