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

This PhD project addresses BBSRC’s ENWW in that the student will be trained in: Biophysical techniques - ITC, SPR, CD; Structural biology techniques - solution state NMR and X-ray crystallography; Computational techniques - molecular dynamics simulations and computer modelling and analysis. Therefore the student will be trained in multidisciplinary areas, applying a wide combination of techniques to study an important molecular system which can be used for novel drug design.

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.

Contact for further details:
[Email Address Removed]
https://www.research.manchester.ac.uk/portal/a.golovanov.html
https://www.research.manchester.ac.uk/portal/andrew.almond.html

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.