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Solving structures of drug targets

Principal Supervisor: Professor Tim Dafforn - School of Biosciences

Co-supervisor: Francisco Fernandez-Trillo, Corinne Smith

PhD project title: Solving structures of drug targets

University of Registration: Birmingham

Project outline:

One of the challenges that remains in protein biochemistry is the production of pure, active membrane proteins. Conventional approaches use detergents to extract these proteins from membranes but the loss of the membrane context often leads to low yields of proteins with low activity. This is particularly frustrating given that membrane proteins remain the major target for drug discovery (e.g. Just one class of membrane protein, GPCRs are the target for 50% of drugs). In 2009 we developed a revolutionary approach to this problem that uses a simple, cost effective reagent, Styrene Maleic Acid co-polymer (SMA) to enable membrane protein production. SMA spontaneously produces nano-scale lipid particles (SMALPs)1-3 from membrane bilayers that include membrane proteins complete with their local membrane environment. We have shown that the method can be successfully applied to the production of a wide range of drug targets (including GPCRs4, ion channels5 and pumps6). We have also found that these SMALP solubilised proteins are perfectly suited to structural studies using X-ray Crystallography, high resolution Cryo-transmission electron microscopy and Small angle scattering (X-ray and Neutron). However we still have some technical challenges before the SMALP proteins can be deployed effectively as part of drug discovery campaigns.

In this project you will:

  1. Develop a new range of SMA molecules that will allow membrane proteins to be used in drug discovery systems
  2. Learn how to use the SMALP technology and apply it to the production of a number of therapeutically relevant membrane proteins (e.g. GPCRs, Ion channels, Pumps). These are chosen in collaboration with a number of industrial partners
  3. Develop methods for using SMALP proteins in systems associated with drug discovery processes
  4. Learn how to solve membrane protein structures using X-ray Crystallography, high resolution Cryo-transmission electron microscopy and Small angle scattering (X-ray and Neutron)

References:

JACS. 2009 Jun 10;131(22):7484-5 3 Nat. Protoc. 2016 Jul;11(7):1149-62. 4Biochem Soc Trans. 2016 Apr 15;44(2):619-23 5PNAS. 2014 Dec 30;111(52):18607-12 6Biochem J. 2014 Jul 15;461(2):269-78

BBSRC Strategic Research Priority: Industrial Biotechnology and Bioenergy

Techniques that will be undertaken during the project:

  • Polymer synthesis
  • Membrane protein expression and purification
  • X-ray crystallography
  • High resolution Cryo-transmission electron microscopy
  • Small angle scattering (X-ray and Neutron)

Contact: Professor Tim Dafforn, University of Birmingham