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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 abundance 1 H,15 N?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.

SUBMITTER: Hewitt SH

PROVIDER: S-EPMC5347857 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Hewitt Sarah H SH Filby Maria H MH Hayes Ed E Kuhn Lars T LT Kalverda Arnout P AP Webb Michael E ME Wilson Andrew J AJ

Chembiochem : a European journal of chemical biology 20161219 2

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 per ...[more]

PMID: 27860106

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Project description:Toxoplasma gondii is an obligate intracellular parasite which can cause toxoplasmosis. Surface and secreted proteins of T. gondii play important roles in infection and immunity, and also are antigen targets in immunological diagnosis and vaccine development. However, it is difficult to investigate identities and antigenicities of surface and secreted proteins due to limitation of surface protein extraction methods. In this study, a total of 785 potential surface and secreted proteins of T. gondii RH tachyzoites were identified using a method combination of biotin labeling, avidin chromatography isolation, and high flux proteomics (LC-MS/MS). Among the highly-expressed 65 proteins, 43 proteins (66%) were originally annotated as surface or secreted proteins in the released T. gondii genomes, which proved the method combination to be a credible strategy. Furthermore, the transcriptomic responses and cytokine secretions induced by the isolated proteins, the live T. gondii RH tachyzoites infection, and the live pathogenic E. coli infection, in the human peripheral blood monocyte THP-1 cell lines, were comparatively analyzed to reveal antigenicities and immunobiological properties of T. gondii surface and secreted proteins. The transciptomic profiles induced by the isolated proteins were similar to those induced by the live bacterium infection, but were different from those induced by the live parasite infection. Contrary to the low cytokine secretion induced by the live parasite infection, the isolated proteins induced significant cytokine and chemokines secretion. Especially, the secretions of several chemokines induced by the isolated proteins were even higher than those induced by the live bacterium infection. These data suggested that T. gondii surface and secreted proteins were effective antigens, while the live parasite could evade the host innate immunity. This study comprehensively revealed the identities and antigenicities of T. gondii surface and secreted proteins, which laid foundation for further screening new T. gondii antigens, developing immunological diagnosis methods, and studying host immune response to T. gondii infection.

Dataset Information

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

Publications

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

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