Fcab-HER2 Interaction: a Ménage à Trois. Lessons from X-Ray and Solution Studies

Structure
Elisabeth LobnerChristian Obinger

Abstract

The crystallizable fragment (Fc) of the immunoglobulin class G (IgG) is an attractive scaffold for the design of novel therapeutics. Upon engineering the C-terminal loops in the CH3 domains, Fcabs (Fc domain with antigen-binding sites) can be designed. We present the first crystal structures of Fcabs, i.e., of the HER2-binding clone H10-03-6 having the AB and EF loop engineered and the stabilized version STAB19 derived by directed evolution. Comparison with the crystal structure of the Fc wild-type protein reveals conservation of the overall domain structures but significant differences in EF-loop conformations. Furthermore, we present the first Fcab-antigen complex structures demonstrating the interaction between the engineered Fcab loops with domain IV of HER2. The crystal structures of the STAB19-HER2 and H10-03-6-HER2 complexes together with analyses by isothermal titration calorimetry, SEC-MALS, and fluorescence correlation spectroscopy show that one homodimeric Fcab binds two HER2 molecules following a negative cooperative binding behavior.

Citations

Aug 1, 2019·The Journal of Biological Chemistry·Kathrin GöritzerRichard Strasser
Oct 14, 2020·Scientific Reports·Teiko Shibata-SekiToshihiro Akaike
Dec 19, 2020·Computational and Structural Biotechnology Journal·Yuanli SongZheng Jian Li
Dec 17, 2019·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Hannah R ReeseStefano Menegatti
Mar 16, 2021·Biochemistry and Biophysics Reports·Filippo BenedettiGordana Wozniak-Knopp
Mar 21, 2021·Biophysical Journal·Louise PinetCarine van Heijenoort
Apr 14, 2021·International Journal of Biological Macromolecules·Daniele UbbialiArio de Marco
Aug 4, 2021·Physical Chemistry Chemical Physics : PCCP·Fabian SoltermannPhilipp Kukura
Feb 28, 2018·Biochemistry·Suvobrata ChakravartyMona Alshamrani
Aug 11, 2021·The EMBO Journal·David HoffmannJosef M Penninger

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