‘Smart materials’ that make proteins form crystals to boost research into new drugs

Thursday 30 June 2011

The process of developing a new drug normally works by identifying a protein that is involved in the disease, then designing a molecule that will interact with the protein to stimulate or block its function. In order to do this, scientists need to know the structure of the protein that they are targeting.
A technique called X-ray crystallography can be used to analyse the arrangement of atoms within a crystal of protein, but getting a protein to come out of solution and form a crystal is a major obstacle. The number of proteins identified as potential drug targets is increasing exponentially as scientists make progress in the fields of genomics and proteomics, but with current methods, scientists have successfully obtained useful crystals for less than 20 per cent of proteins that have been tried.
Researchers at University of Surrey with colleagues at Imperial College London have developed a more effective method for making proteins crystallise using materials called ‘molecularly imprinted polymers’ (MIPs). MIPs are compounds made up of small units that bind together around the outside of a molecule. When the molecule is extracted, it leaves a cavity that retains its shape and has a strong affinity for the target molecule.
This property makes MIPs ideal nucleants – substances that bind protein molecules and make it easier for them to come together to form crystals. Many substances have been used as nucleants before, but none are designed specifically to attract a particular protein.
Dr Subrayal M Reddy, Senior Lecturer in Applied Analytical Chemistry at the University of Surrey, said: “To date, surfaces used for protein crystallization have been random at best with no rational design. For the first time, we have introduced specific protein architecture in the form of our smart materials - molecularly imprinted polymers (MIPs).

"This is an enabling technology which will facilitate genomic and proteomic research and the discovery of new drugs."

The ability to get good enough quality protein crystals to determine protein structure and function has been a major obstacle so far, but with MIPs, we are able to get

• better protein crystals with improved X-ray resolution

• crystals, in cases where protein crystals are difficult to grow or would not grow at all - Six different MIPs crystallised nine proteins under conditions that otherwise do not produce crystals. In 10 per cent of trials, the compounds also succeeded in crystallising three troublesome proteins that failed preliminary crystallisation attempts.

• faster protein crystal growth in some cases

The study found that six different MIPs induced crystallisation of nine proteins, yielding crystals in conditions that do not give crystals otherwise. Researchers also tested whether MIPs would be effective at producing crystals from a series of preliminary trials for three target proteins for which scientists have not previously been able to obtain crystals of sufficient quality. The presence of MIPs gave rise to crystals in eight to 10 per cent of such trials, yielding valuable crystals that would have been missed using other known nucleants.
The research was funded by the Engineering and Physical Sciences Research Council (EP/G014299/1 and EP/G014736/1) and the European Commission.

Notes to editors:
Journal reference: Saridakis et al. ‘Protein crystallization facilitated by molecularly imprinted polymers’ Proceedings of the National Academy of Sciences, published online 20 June 2011.
The Engineering and Physical Sciences Research Council (EPSRC) is the UK’s main agency for funding research in engineering and physical sciences. EPSRC invests around £800m a year in research and postgraduate training, to help the nation handle the next generation of technological change. The areas covered range from information technology to structural engineering, and mathematics to materials science. This research forms the basis for future economic development in the UK and improvements for everyone’s health, lifestyle and culture. EPSRC works alongside other Research Councils with responsibility for other areas of research. The Research Councils work collectively on issues of common concern via research Councils UK.

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