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Structural insights into the non-inhibitory mechanism of the anti-EGFR EgB4 nanobody

DOI: 10.1186/s12860-022-00412-x DOI Help

Authors: Matthieu R. Zeronian (Utrecht University) , Sofia Doulkeridou (Utrecht University) , Paul M. P. Van Bergen En Henegouwen (Utrecht University) , Bert J. C. Janssen (Utrecht University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Bmc Molecular And Cell Biology , VOL 23

State: Published (Approved)
Published: March 2022
Diamond Proposal Number(s): 19800

Open Access Open Access

Abstract: Background: The epidermal growth factor receptor (EGFR) is involved in various developmental processes, and alterations of its extracellular segment are associated with several types of cancers, in particular glioblastoma multiforme (GBM). The EGFR extracellular region is therefore a primary target for therapeutic agents, such as monoclonal antibodies and variable domains of heavy chain antibodies (VHH), also called nanobodies. Nanobodies have been previously shown to bind to EGFR, and to inhibit ligand-mediated EGFR activation. Results: Here we present the X-ray crystal structures of the EgB4 nanobody, alone (to 1.48 Å resolution) and bound to the full extracellular EGFR-EGF complex in its active conformation (to 6.0 Å resolution). We show that EgB4 binds to a new epitope located on EGFR domains I and II, and we describe the molecular mechanism by which EgB4 plays a non-inhibitory role in EGFR signaling. Conclusion: This work provides the structural basis for the application of EgB4 as a tool for research, for targeted therapy, or as a biomarker to locate EGFR-associated tumors, all without affecting EGFR activation.

Journal Keywords: Nanobody; Receptor; Structure; X-ray diffraction; EGFR-EGF

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 07/03/2022 09:56

Documents:
s12860-022-00412-x.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)