Version 1
: Received: 22 September 2024 / Approved: 23 September 2024 / Online: 24 September 2024 (05:01:12 CEST)
How to cite:
Konshina, A. G.; Bocharov, E. V.; Konovalova, E. V.; Schulga, A. A.; Tolmachev, V.; Deyev, S. M.; Efremov, R. G. Structural Basis of the Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains. Preprints2024, 2024091790. https://doi.org/10.20944/preprints202409.1790.v1
Konshina, A. G.; Bocharov, E. V.; Konovalova, E. V.; Schulga, A. A.; Tolmachev, V.; Deyev, S. M.; Efremov, R. G. Structural Basis of the Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains. Preprints 2024, 2024091790. https://doi.org/10.20944/preprints202409.1790.v1
Konshina, A. G.; Bocharov, E. V.; Konovalova, E. V.; Schulga, A. A.; Tolmachev, V.; Deyev, S. M.; Efremov, R. G. Structural Basis of the Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains. Preprints2024, 2024091790. https://doi.org/10.20944/preprints202409.1790.v1
APA Style
Konshina, A. G., Bocharov, E. V., Konovalova, E. V., Schulga, A. A., Tolmachev, V., Deyev, S. M., & Efremov, R. G. (2024). Structural Basis of the Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains. Preprints. https://doi.org/10.20944/preprints202409.1790.v1
Chicago/Turabian Style
Konshina, A. G., Sergey M. Deyev and Roman G. Efremov. 2024 "Structural Basis of the Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains" Preprints. https://doi.org/10.20944/preprints202409.1790.v1
Abstract
Non-immunoglobulin based scaffold proteins (SPs) represent one of the key therapeutic target-specific and high-affinity binders in modern medicine. Among their cellular targets are signaling receptors, in particular, receptor tyrosine kinases, whose dysfunction leads to the development of cancer and other serious diseases. Successful applications of SPs have been reported for HER receptor type 2 (HER2), the member of the human epidermal growth factor receptor family that regulates the cell growth and differentiation. To extend blood residence of SPs and prevent their high accumulation in kidney, these proteins are often fused with serum albumin. Promising results for the HER2-binding activity were obtained for SP G3 from DARPins (Designed Ankyrin Repeat Proteins) family fused with albumin-binding domain (ABD) [1]. Interestingly, detected HER2-G3 binding strongly depended on the position of G3 module in the sequence of the constructs. Further improvement of these constructs for biomedical applications requires deciphering the molecular mechanism responsible for this effect. Here, we investigate the structural and dynamic aspects of ABD-G3 and G3-ABD chimeras using NMR spectroscopy and molecular modeling. Based on biophysical data, we came to the conclusion that extensive interdomain contacts form in both constructs, although the binding interfaces and complex stability are somewhat different. Also, it was shown that the domain linker plays an important role – it limits the accessibility of detected protein-protein binding sites depending on the order of the domains in chimeric molecules. The results create a solid structural basis for the rational design of new effective SP-constructs targeting signaling receptor in the cell.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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