Molecular modeling based mutagenesis defines ligand binding and specificity determining regions of fibroblast growth factor receptors

Biochemistry
T E GrayA Yayon

Abstract

The fibroblast growth factor receptor 2 (FGFR2) and the keratinocyte growth factor receptor (KGFR) have different ligand binding specificities despite differing only in the second half of their immunoglobulin-like (Ig-like) domain III. Three-dimensional model structures were generated for domain III on the basis of variable (V) Ig domains. The region that differs between the two receptors is predicted to include two loops: one connects beta-strands F-G and is analogous to the complementarity determining region 3 (CDR3) of immunoglobulins; the other connects beta-strands D-E. These regions were targeted for mutagenesis. Single mutations in the F-G loop were found to only slightly alter ligand binding, whereas a double mutant, KGFR Y345-->S,Q348-->I, acquired significant affinity for bFGF. Notably, the affinity of this double mutant KGFR for KGF and aFGF was essentially unaltered. A mutant FGFR2, in which the D-E beta-hairpin (T319TDKEI) is replaced with the KGFR D-E beta-hairpin (S319SNA), has 9-fold reduced affinity for bFGF. These results demonstrate that the F-G or CDR3 analogous loop in FGFRs plays a key role in determining ligand binding and specificity. In addition, however, the protein loop connecting beta-strands D and E...Continue Reading

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Citations

Dec 1, 1995·Nature Structural Biology·A Bateman, C Chothia
Aug 8, 2002·Hybridoma and Hybridomics·Vincent D BlanckaertMargaret E Schelling
Jun 24, 1997·Proceedings of the National Academy of Sciences of the United States of America·J RayF H Gage
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Apr 24, 2010·Journal of Cellular and Molecular Medicine·Xiaoping WuXiaokun Li
Dec 18, 2004·Biomaterials·Solitaire A DeLongJennifer L West
Feb 28, 2019·Frontiers in Genetics·Allen Zinkle, Moosa Mohammadi

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