Interactions of a hybrid insulin/insulin-like growth factor-I analog with chimeric insulin/type I insulin-like growth factor receptors.
We have examined, by use of a hybrid insulin/insulin-like growth factor-I analog and chimeric insulin/type I insulin-like growth factor receptors, the interplay between ligand and receptor structure in determining the affinity and specificity of hormone-receptor interactions in the insulin and insulin-like growth factor-I systems. Our findings, obtained through the study of radiolabeled peptide binding to detergent-solubilized full-length receptors and to soluble truncated receptors, show that (a) the two-chain hybrid analog exhibits significant cross-reactivity with both receptor systems, (b) the exchange of appropriate domains in chimeric receptors enhances the receptor binding affinity of the analog by 3.5-21-fold, and (c) the affinity of the hybrid analog for the chimeric receptors actually exceeds that of either natural insulin or natural insulin-like growth factor-I. We conclude that the specificity-conferring domains of the insulin and type I insulin-like growth factor receptors reside in different regions of a common binding site, and that the exchange of domains between pairs of related hormones and between pairs of related receptors can yield new ligand-receptor systems with significantly altered affinities and selectivities.
Schäffer
L
L
Department of Diabetes Research, Novo Nordisk A/S, Bagsvaerd, Denmark.
Kjeldsen
T
T
Andersen
A S
AS
Wiberg
F C
FC
Larsen
U D
UD
Cara
J F
JF
Mirmira
R G
RG
Nakagawa
S H
SH
Tager
H S
HS
D001665:Binding Sites; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008961:Models, Structural; D055503:Protein Multimerization; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D017384:Sequence Deletion
D007328:Insulin; D008024:Ligands; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1