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A nanotechnology solution to one of drug discovery’s last challenges.


Project Description

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 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) for the production of 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. Since this time we have shown that the SMALP methods in generically applicable to a wide range of membranes proteins including G-protein coupled receptors, ion channels, pumps and enzymes. 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 bio-therapeutic discovery pipelines. In this project we will work with Medimmune to develop the SMALP for use in their bio-therapeutic discovery campaigns pipeline. This will include:

1) Developing the SMALP method for production of targets proposed by Medimmune
2) Using physical techniques (e.g. Neutron, X-ray and light scattering) to understand the physical principles that underpin the SMALP process
3) Developing custom polymers (in partnership with Francisco Fernandez-Trillo, chemistry) to enable tethering of SMALPs to surfaces for drug discovery assays and structural biology methods essential for structure-based drug design

Together these elements will help Medimmune to include new targets, not previously available using traditional methods, in their bio-therapeutic discovery programs.

Funding Notes

The project is part of the BBSRC MIBTP programme, involving the Universities of Warwick, Birmingham and Leicester.

More details on this fully funded 4-year PhD programme, can be found at View Website

More details on eligibility requirements may be found on View Website

References

Purification of membrane proteins free from conventional detergents: SMA, new polymers, new opportunities and new insights.
Stroud Z, Hall SCL, Dafforn TR. Methods. 2018 Sep 1;147:106-117.

A method for detergent-free isolation of membrane proteins in their local lipid environment. Lee SC, Knowles TJ, Postis VL, Jamshad M, Parslow RA, Lin YP, Goldman A, Sridhar P, Overduin M, Muench SP, Dafforn TR. Nat Protoc. 2016 Jul;11(7):1149-62

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

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