Title : Structural basis for high-affinity
HER2 receptor binding by an engineered
protein
Abstract :
- The human epidermal growth factor receptor 2 ( HER2 ) is specifically overexpressed in tumors of several cancers, including an aggressive form of breast cancer
- It is therefore a target for both cancer diagnostics and therapy
- The 58 amino acid residue Zher2 affibody molecule was previously engineered as a high-affinity binder of HER2
- Here we determined the structure of Zher2 in solution and the crystal structure of Zher2 in complex with the HER2 extracellular domain
- Zher2 binds to a conformational epitope on HER2 that is distant from those recognized by the therapeutic antibodies trastuzumab and pertuzumab
- Its small size and lack of interference may provide Zher2 with advantages for diagnostic use or even for delivery of therapeutic agents to HER2-expressing tumors when trastuzumab or pertuzumab are already employed
- Biophysical characterization shows that Zher2 is thermodynamically stable in the folded state yet undergoing conformational interconversion on a submillisecond time scale
- The data suggest that it is the HER2-binding conformation that is formed transiently prior to binding
- Still, binding is very strong with a dissociation constant K(D) = 22 pM, and perfect conformational homogeneity is therefore not necessarily required in engineered binding proteins
- A comparison of the original Z domain scaffold to free and bound Zher2 structures reveals how high-affinity binding has evolved during selection and affinity maturation and suggests how a compromise between binding surface optimization and stability and dynamics of the unbound state has been reached
Output (sent_index, trigger,
protein,
sugar,
site):
Output(Part-Of) (sent_index,
protein,
site):
- 3. HER2, residue
- 4. HER2, domain
- 5. HER2, epitope
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):