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(BBSRC DTP) Inhibition of SR protein kinase 1 with designer peptides


Project Description

Protein-protein interactions (PPIs) have fundamental biological importance, and using inhibitors to block their biological networks in a pathway-defined manner is a major pharmaceutical goal. Peptides are a novel class of protein-based biopharmaceuticals that are ideally suited to the specific PPI inhibition task, but methods need to be developed for their targeted design.

Serine-arginine (SR) protein kinase 1 (SRPK1), a regulator of alternative mRNA splicing, has recently been recognized as an extremely important drug target and is also an excellent model system for studying PPI inhibition. Developing a strategy for blocking interactions between SRPK1 and native substrates, while important in its own right, is also a significant step to finding generic approaches for specific inhibition of PPIs. We have recently identified a viral peptide that binds to the SRPK1, and started to build up a detailed structural and mechanistic understanding of this system from crystallography and biophysical characterisation. The tight binding of this peptide offers an excellent starting point to develop the longer, more specific and potent peptides that occupy the substrate binding site, needed to inhibit SRPK1.

The Aim of the current study is to develop a strategy for the design of peptide-based inhibitors that bind SRPK1 in a substrate-competitive manner. The student will join an ambitious project aiming to develop a general strategy for inhibiting PPIs with therapeutic peptides, and will get extensive training in the combination of structural biology, computational science, biophysical characterisation and peptide-based drug design.

http://www.manchester.ac.uk/research/A.Golovanov/
http://www.manchester.ac.uk/research/Andrew.Almond/

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] Tunnicliffe RB, Lockhart-Cairns MP, Levy C, Mould AP, Jowitt TA, Sito H, Baldock C, Sandri-Goldin RM, Golovanov AP. 2017. The herpes viral transcription factor ICP4 forms a novel DNA recognition complex. Nucleic Acids Res. 45(13):8064-8078.
[2] Tunnicliffe RB, Collins RF, Ruiz Nivia HD, Sandri-Goldin RM, Golovanov AP. 2018. The ICP27 Homology Domain of the Human Cytomegalovirus Protein UL69 Adopts a Dimer-of-Dimers Structure. MBio. 9(3). pii: e01112-18.
[3]Tunnicliffe RB, Levy C, Ruiz Nivia HD, Sandri-Goldin RM, Golovanov AP. 2018. Structural identification of conserved RNA binding sites in herpesvirus ORF57 homologs: implications for PAN RNA recognition. Nucleic Acids Res. 47 (4), 1987-2001
[4] Almond, A. 2018. Multiscale modeling of glycosaminoglycan structure and dynamics: current methods and challenges. Curr Opin Struct Biol, 50, pp. 58-64. DOI: 10.1016/j.sbi.2017.11.008.
[5] Tunnicliffe RB, Tian X., Storer J., Sandri-Goldin RM, Golovanov AP. 2018. Overlapping motifs on the herpes viral proteins ICP27 and ORF57 mediate interactions with the mRNA export adaptors ALYREF and UIF. Scientific Reports, 8 (1), 15005

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