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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Interaction of antibodies with ErbB receptor extracellular regions
Karl R Schmitz1, Kathryn M Ferguson
1Department of Physiology, University of Pennsylvania School of Medicine, B400 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085, USA.
Abstract:
Antibodies to the extracellular region of the ErbB receptors have played key roles in the development of a mechanistic understanding of this family of receptor tyrosine kinases. An extensively studied class of such antibodies inhibits activation of ErbB receptors, and these antibodies have been the focus of intense development as anti-cancer agents. In this review we consider the properties of ErbB receptors antibodies in light of the current structure-based model for ErbB receptor homo- and hetero-dimerization and activation. Crystal structures of the Fab fragments from five different inhibitory antibodies in complex with the extracellular regions of EGFR and ErbB2 have been determined. These structures highlight several different modes of binding and mechanisms of receptor inhibition. Information about antibody interactions with the structurally well-characterized soluble extracellular regions of ErbB receptors can be combined with the rich knowledge of the effects of these antibodies in cultured cells, and in vivo, to provide insights into the conformation and activation of ErbB receptors at the cell surface.
Insights
Antibodies targeting ErbB receptors provide key insights into receptor tyrosine kinase function. Structural studies reveal diverse binding mechanisms for these inhibitory antibodies, crucial for anti-cancer drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- ErbB receptor tyrosine kinases are critical in cellular signaling and cancer.
- Antibodies targeting ErbB receptors are vital for understanding their function and developing cancer therapies.
- A structure-based model for ErbB receptor dimerization and activation is currently available.
Purpose of the Study:
- To review the properties of ErbB receptor antibodies in the context of current structural models.
- To elucidate the binding modes and inhibition mechanisms of inhibitory antibodies against ErbB receptors.
Main Methods:
- Analysis of crystal structures of antibody Fab fragments bound to extracellular domains of EGFR and ErbB2.
- Integration of structural data with existing knowledge of antibody effects in cellular and in vivo models.
Main Results:
- Determined crystal structures for five distinct inhibitory antibodies complexed with EGFR and ErbB2 extracellular regions.
- Identified multiple binding modes and inhibitory mechanisms employed by these antibodies.
- Demonstrated how structural information complements functional data to understand cell surface receptor activation.
Conclusions:
- Structural insights into antibody-ErbB interactions provide a deeper understanding of receptor conformation and activation.
- This knowledge is crucial for the rational design of targeted cancer therapies.
- Antibody-based studies continue to advance the mechanistic understanding of ErbB receptor signaling.
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