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Nietlispach Group

NMR spectroscopy of membrane proteins

Studying at Cambridge

 

Research

Integral membrane proteins: structure, dynamics and function

 

Membrane proteins represent approximately 35% of all the proteins in the genome but their native membrane environment makes them difficult targets to study. Despite their large abundance they are structurally underrepresented and account for less than 0.5% of solved 3D structures. 

Our group is interested in the study of 7-helical membrane proteins such as microbial rhodopsin and the large family of eukaryotic G protein-coupled receptors (GPCRs). GPCRs are physiologically important membrane proteins at the cell surface that sense signalling molecules such as hormones and neurotransmitters and are the targets of a multitude of prescribed drugs. Upon ligand binding GPCRs undergo conformational changes, causing the activation of complex cytosolic signalling networks, which result in a cellular response. 

Recent advances in the field of GPCR structural biology have provided unprecedented insights into the structural and functional diversity of this protein family. However, the information derived so far from X-ray crystallography studies conveys a static picture, whereas these proteins are highly dynamic and interconvert between various states of different activity. How these changes occur is currently poorly understood.

Over recent years NMR spectroscopy has developed into a powerful technique to study the structure and function of such proteins. One of the distinct advantages of NMR spectroscopy is its versatility as the method can equally report on molecular structure, ligand binding, conformational changes and dynamical processes that can take place on a wide range of timescales.

We are using NMR spectroscopy to explore the dynamic landscape of membrane proteins during signalling. Understanding the changes in conformational dynamics during receptor activation is key to comprehend how these molecules signal and how disease resulting from aberrant signalling can be treated for example through rational drug design. We also develop biological and NMR-based tools to facilitate this work, such as investigating new membrane-mimicking media as well as expanding the experiments available for NMR studies of membrane proteins.

More information on specific projects can be found by following the links.