{"@context":"https://schema.org","@type":"ScholarlyArticle","headline":"Structural basis for high-affinity HER2 receptor binding by an engineered protein","author":[{"@type":"Person","name":"C. Eigenbrot"},{"@type":"Person","name":"M. Ultsch"},{"@type":"Person","name":"A. Dubnovitsky"},{"@type":"Person","name":"L. Abrahmsén"},{"@type":"Person","name":"T. Härd"}],"datePublished":"2010","isPartOf":{"@type":"Periodical","name":"Proceedings of the National Academy of Sciences"},"identifier":"https://doi.org/10.1073/pnas.1005025107","description":"\n 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 Z\n her\n 2 affibody molecule was previously engineered as a high-affinity binder of HER2. Here we determined the structure of Z\n her\n 2 in solution and the crystal structure of Z\n her\n 2 in complex with the HER2 extracellular domain. Z\n her\n 2 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 Z\n her\n 2 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 Z\n her\n 2 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\n K\n \n D\n \n = 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 Z\n her\n 2 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.\n ","url":"https://innscience.ca/es/community/literature/ccacff39-f7aa-4db0-9910-8b56615acc86"}