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Daniel Nietlispach

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 the solved 3D structures. 

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 using NMR spectroscopy over other structure determination techniques 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.

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 signaling 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 from a static picture, whereas these proteins are highly dynamic and interconvert between various states of different activity. How these changes occur is currently little understood and we are using NMR spectroscopy to explore this dynamic receptor landscape. Understanding the changes in the conformational dynamics during receptor activation is key to comprehend how these molecules signal and how disease resulting from aberrant signaling can be treated through e.g. rational drug design. 

Lab members:

Mark Bostock, Henry Chien, Niclas Frei, Prashant Kumar, Andras Solt, Yi Lei Tan, Yvonne Yu, Rowina Westermeier

Key publications:

1. Gautier, A., Kirkpatrick, J.P. and Nietlispach, D. (2008) Solution-state NMR spectroscopy of a seven-helix transmembrane protein receptor: Backbone assignment, secondary structure, and dynamics. Angew. Chem.-Int. Edit. 47, 7297-7300.

2. Gautier, A., Mott, H.R., Bostock, M.J., Kirkpatrick, J.P. and Nietlispach, D. (2010) Structure determination of the seven-helix transmembrane receptor sensory rhodopsin II by solution NMR spectroscopy. Nat. Struct. Mol. Biol. 17, 768-774.

3. Holland, D.J., Bostock, M.J., Gladden, L.F. and Nietlispach, D. (2011) Fast Multidimensional NMR Spectroscopy Using Compressed Sensing. Angew. Chem.-Int. Edit. 50, 6548-6551.

4. Crick, D.J, Wang, J.X., Graham, B., Swarbrick, J.D., Mott, H.R. and Nietlispach, D. (2015) Integral membrane protein structure determination using pseudocontact shifts. J Biomol NMR 61, 197-207.