3MZW

HER2 extracelluar region with affinity matured 3-helix affibody ZHER2:342

3MZW の概要

• エントリーDOI: 10.2210/pdb3mzw/pdb
• 分子名称: Tyrosine kinase-type cell surface receptor HER2, Immunoglobulin G-binding protein A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: protein-protein complex, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76375.46

構造登録者

Eigenbrot, C.,Ultsch, M.H. (登録日: 2010-05-13, 公開日: 2010-07-28, 最終更新日: 2024-10-30)

主引用文献

Eigenbrot, C.,Ultsch, M.,Dubnovitsky, A.,Abrahmsen, L.,Hard, T.
Structural basis for high-affinity HER2 receptor binding by an engineered protein.
Proc.Natl.Acad.Sci.USA, 107:15039-15044, 2010

PubMed 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.

PubMed: 20696930
DOI: 10.1073/pnas.1005025107

実験手法

X-RAY DIFFRACTION (2.9 Å)