Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins

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• 作者：Sarah H. Hewitt ; Dr. Maria H. Filby ; Dr. Ed Hayes ; Dr. Lars T. Kuhn ; Dr. Arnout P. Kalverda ; Dr. Michael E. Webb and Prof. Andrew J. Wilson
• 刊名：ChemBioChem
• 出版年：2017
• 出版时间：January 17, 2017
• 年：2017
• 卷：18
• 期：2
• 页码：223-231
• 全文大小：1460K
• ISSN：1439-7633

文摘

Protein surface mimetics achieve high-affinity binding by exploiting a scaffold to project binding groups over a large area of solvent-exposed protein surface to make multiple cooperative noncovalent interactions. Such recognition is a prerequisite for competitive/orthosteric inhibition of protein–protein interactions (PPIs). This paper describes biophysical and structural studies on ruthenium(II) tris(bipyridine) surface mimetics that recognize cytochrome (cyt) c and inhibit the cyt c/cyt c peroxidase (CCP) PPI. Binding is electrostatically driven, with enhanced affinity achieved through enthalpic contributions thought to arise from the ability of the surface mimetics to make a greater number of noncovalent interactions than CCP with surface-exposed basic residues on cyt c. High-field natural abundance ¹H,¹⁵N HSQC NMR experiments are consistent with surface mimetics binding to cyt c in similar manner to CCP. This provides a framework for understanding recognition of proteins by supramolecular receptors and informing the design of ligands superior to the protein partners upon which they are inspired.