Chemical probes to study phosphohistidine

Lead Research Organisation: University of Leeds
Department Name: Sch of Chemistry


Phosphohistidine is a protein post-translational modification that has historically been neglected due to its instability towards standard analytical techniques. The recent synthesis of stable phosphohistidine analogues has enabled production of antibodies recognizing the modification. These have then been used to demonstrate widespread phosphohistidine modification throughout the proteome of different species, from bacteria to mammals. This suggests that many uncharacterised biological pathways rely on this elusive modification.

This project will involve the synthesis of the next generation of chemical probes for the study of histidine phosphorylation. We will determine whether the existing chemical mimics of phosphohistidine can recapitulate the function of the native modified amino-acid in its biological context as well as generating the next generation of chemical probes to enable identification of phosphohistidine-binding and modifying proteins.

We will generate peptidic probes containing existing and new classes of phosphohistidine analogue and use chemical proteomics approaches to evaluate which classes of analogue can be used to drive interaction with native phosphohistidine-interacting proteins. These classes of analogue will then be used by the student to profile phosphohistidine-interacting proteins in bacterial and metazoan cells.

The development of chemical tools and analytical approaches to study protein modifications greatly accelerates understanding of this fundamental biology and its potential manipulation for societal benefit. For example, 30 years ago the related modification phosphotyrosine was similarly under-studied, and yet now, due to intense interdisciplinary research efforts including development of novel tools, anti-cancer drugs targeting this modification are in clinical use.

This project falls within the EPSRC research areas of "Chemical biology and biological chemistry" and "analytical science". The project will provide training in organic and peptide synthesis, biochemical methods including protein chemistry, and mass spectrometry-based proteomics.


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