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Molecular Cookie Cutters: Cutting Edge Drug Discovery using G-Protein Coupled Receptors


School of Biosciences

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Prof Tim Dafforn No more applications being accepted Funded PhD Project (European/UK Students Only)

About the Project

Membrane proteins represent 30-40% of the cellular proteome and carry out a wide range of fundamental biological process. These include sensing the outside world, helping maintain cellular structure and homeostasis. Despite their clear importance, progress in understanding their function at a molecular level has been slow. Currently less than 5% of protein structures that are known are from membrane proteins. The reason for this is simple, membrane proteins have evolved to have stable structures only in membranes and are not at all stable in the aqueous solutions used for most structural and function studies. Historically, to address this issue scientists have used detergents to help stabilise these delicate proteins in aqueous solution. However, detergents have provided only an incomplete and imperfect solution, with most membrane proteins showing little or no activity in detergent.

In 2009 we developed a revolutionary new polymer-based method (SMALP), also known as a molecular cookie cutter, to produce the membrane proteins. The method negates the problematic use of detergents in making membrane proteins, instead encapsulating them, complete with a portion of phospholipid membrane in a 10 nm diameter nanodisc. We have shown that the SMALP methods in generically applicable to a wide range of membranes proteins ranging from G-protein coupled receptors (GPCRs) to receptors used to allow viruses (like COVID-19) entry to cells. The resulting preparations show a high degree of activity and a stability that is substantially enhanced over detergent purified samples. These observations have made the method an ideal one for use in drug discovery meaning that there has been significant interest from a wide range of pharmaceutical companies who see it as a way of relieving a crucial bottleneck in their therapeutic discovery pipelines. In this project we will work with Domainex Ltd to develop the SMALP for use in their therapeutic discovery campaigns pipelines involving GPCRs.

This project will include:

1) Using our SMALP system to produce membrane proteins that are drug targets

2) Developing improved SMALP systems that allow a wider range of drug targets to be produced and tested.

3) Studying the structure and function of these proteins using a range of techniques including SPR and Cryo-EM

Together these elements will show that polymer-solubilisation renders otherwise intractable drug targets accessible to the biophysical and structural methods needed to drive therapeutic discovery programs. In particular, Domainex is developing a generic biophysical drug discovery platform for GPCR targets, and the neurotensin 1 receptor can be used as an early test case.

Funding Notes

Studentship includes: fees, a tax free stipend of at least £15,009 p.a (to rise in line with UKRI recommendation); a travel allowance in year 1; a travel / conference budget; a generous consumables budget and use of a MacBook Pro for the duration of the programme.

References

Membrane proteins solubilized intact in lipid containing nanoparticles bounded by styrene maleic acid copolymer. Knowles TJ1, Finka R, Smith C, Lin YP, Dafforn T, Overduin M. J Am Chem Soc. 2009 Jun 10;131(22):7484-5

Encapsulated membrane proteins: A simplified system for molecular simulation. Lee SC, Khalid S, Pollock NL, Knowles TJ, Edler K, Rothnie AJ, R T Thomas O, Dafforn TR. Biochim Biophys Acta. 2016 Oct;1858(10):2549-2557.
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