title: Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins.
abstract: 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 abundance1H,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.
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.|Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Hewitt
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.|Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Filby
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.|Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Hayes
authors.affiliation: Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Lars T
authors.initials: LT
authors.lastname: Kuhn
authors.affiliation: Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Arnout P
authors.initials: AP
authors.lastname: Kalverda
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.|Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Webb
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.|Astbury Centre For Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
authors.forename: Andrew J
authors.identifier: http://orcid.org/0000-0001-9852-6366
authors.initials: AJ
authors.lastname: Wilson
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D003578:Cytochrome-c Peroxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D009994:Osmolar Concentration; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D012428:Ruthenium / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D055672:Static Electricity; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D056831:Coordination Complexes; D011994:Recombinant Proteins; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D045304:Cytochromes c; D003578:Cytochrome-c Peroxidase
keywords: molecular recognition; protein surface recognition; protein-protein interactions; receptors; supramolecular chemistry