Abstract
Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER family that is overexpressed in some of the most aggressive tumours. Although it is known that HER2 dimerization involves a specific region of its extracellular domain, the so-called “dimerization arm”, the mechanism of dimerization inhibition remains uncertain. However, uncovering how antibody interactions lead to inhibition of HER2 dimerization is of key importance in understanding its role in tumour progression and therapy. Herein, we employed several computational modelling techniques for a molecular-level understanding of the interactions between HER and specific anti-HER2 antibodies, namely an antigen-binding (Fab) fragment (F0178) and a single-chain variable fragment from Trastuzumab (scFv). Specifically, we investigated the effects of antibody-HER2 interactions on the key residues of “dimerization arm” from molecular dynamics (MD) simulations of unbound HER (in a total of 1 µs), as well as ScFv:HER2 and F0178:HER2 complexes (for a total of 2.5 µs). A deep surface analysis of HER receptor revealed that the binding of specific anti-HER2 antibodies induced conformational changes both in the interfacial residues, which was expected, and in the ECDII (extracellular domain), in particular at the “dimerization arm”, which is critical in establishing protein–protein interface (PPI) interactions. Our results support and advance the knowledge on the already described trastuzumab effect on blocking HER2 dimerization through synergistic inhibition and/or steric hindrance. Furthermore, our approach offers a new strategy for fine-tuning target activity through allosteric ligands.
Highlights
The human epidermal growth factor receptor (EGFR) family comprises four members: human epidermal growth factor 1 (HER1), Human epidermal growth factor 2 (HER2), HER3, and HER4 [1]
In ScFv:HER2, the contribution of ECDIV is reduced, which was assigned to the strong interaction of the scFv with this region (Figure 1B)
We need to evaluate the more conventional structural properties, such as the root-mean-square deviation (RMSD), but we will need to monitor larger conformational transition of the quaternary subunits that may appear at the slower timescales
Summary
The human epidermal growth factor receptor (EGFR) family comprises four members: human epidermal growth factor 1 (HER1), HER2, HER3, and HER4 [1]. They are overexpressed in a wide variety of malignant tumours, in particular in non-small cell lung cancer (NSCLC) (40%–80%), breast cancer (14%–91%), and head and neck cancer (80%–100%) [2]. EGFR became an important biomarker and target of anti-tumour therapy [3]. Within the EGFR family, HER2 is one of the most important members and when overexpressed, represents one of the most aggressive phenotypes (approximately 20%–25% of invasive breast cancers) [4], making HER2 a well-established therapeutic target. It is noteworthy that HER2 is the only member of the EGFR family that does not homodimerize under normal conditions, and its ectodomain does not directly bind ligands [9]
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