Convergent solutions to binding at a protein-protein interface.
The hinge region on the Fc fragment of human immunoglobulin G interacts with at least four different natural protein scaffolds that bind at a common site between the C(H2) and C(H3) domains. This "consensus" site was also dominant for binding of random peptides selected in vitro for high affinity (dissociation constant, about 25 nanomolar) by bacteriophage display. Thus, this site appears to be preferred owing to its intrinsic physiochemical properties, and not for biological function alone. A 2.7 angstrom crystal structure of a selected 13-amino acid peptide in complex with Fc demonstrated that the peptide adopts a compact structure radically different from that of the other Fc binding proteins. Nevertheless, the specific Fc binding interactions of the peptide strongly mimic those of the other proteins. Juxtaposition of the available Fc-complex crystal structures showed that the convergent binding surface is highly accessible, adaptive, and hydrophobic and contains relatively few sites for polar interactions. These are all properties that may promote cross-reactive binding, which is common to protein-protein interactions and especially hormone-receptor complexes.
DeLano
W L
WL
Graduate Group in Biophysics, University of California, San Francisco, CA 94143, USA and Sunesis Pharmaceuticals, 3696 Haven Avenue, Suite C, Redwood City, CA 94063, USA.
Ultsch
M H
MH
de Vos
A M
AM
Wells
J A
JA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001666:Binding Sites, Antibody; D018360:Crystallography, X-Ray; D019281:Dimerization; D019143:Evolution, Molecular; D006801:Humans; D006860:Hydrogen Bonding; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry / Q000378:metabolism*; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000737:chemistry / Q000378:metabolism; D012217:Rheumatoid Factor / Q000737:chemistry / Q000378:metabolism; D013205:Staphylococcal Protein A / Q000378:metabolism
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011961:Receptors, Fc; D013205:Staphylococcal Protein A; D012217:Rheumatoid Factor