Søren Gøgsig Faarup Rasmussen – University of Copenhagen

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Søren Gøgsig Faarup Rasmussen

Associate Professor

Lundbeck Foundation Junior Group Leader
Molecular Neuropharmacology Laboratory
Department of Neuroscience and Pharmacology
Faculty of Health Science

sgfr@sund.ku.dk






Søren G.F. Rasmussen's research is focused on understanding the molecular structure of G-protein-coupled receptors (GCPRs) and the agonist-induced conformational changes that form the basis for their functions.

 Research

Crystal structure of an agonist bound beta2 adrenergic receptor (in blue) on the cell surface in complex with the stimulatory G protein, Gs bound from inside the cell. The heterotrimeric Gs protein is shown in orange, yellow and green for the subunits GalphaS, Gbeta and Ggamma, respectively (Nature, September 29th, 2011 issue)


G-protein-coupled receptors (GPCRs) are an important class of transmembrane proteins located on the surface of virtually all cells where they are responsible for mediating most of our physiological responses towards hormones, neurotransmitters and environmental stimulants. For these reasons, they are major therapeutic targets. Signaling across the cell membrane barrier follows binding of a stimulating hormone (agonist) to the receptor. The agonist facilitates the GPCR to undergo conformational changes that allow G proteins to dock the receptor on the intracellular side. The interaction with the receptor activates the G protein, which subsequently regulates downstream effector proteins that orchestrate the cells physiological response. Due to their ubiquitous nature, solving crystal structures of G-protein-coupled receptors (GPCRs) holds potential for developing many new and improved pharmaceuticals with better action and fewer side effects through application of structure-based drug discovery.

In my lab, research is focused on understanding the molecular structure of GPCRs and the agonist-induced conformational changes that form the basis for their functions. In order to understand these signal-transduction events in detail, we work to solve crystal structures of selected GPCRs in various functional states ranging from inhibitor bound inactive states, over partially active states, to fully active states in complex with their particular G-protein subtype. In addition to X-ray crystallography we study ligand-induced conformational changes and oligomerization behavior of the beta2 adrenergic G protein coupled receptor by various single molecule fluorescence spectroscopy techniques in collaboration with the research groups of Dimitrios Stamou and Nikos Hatzakis.

 
CV

2011-present Assistant Professor and Lundbeck Foundation Junior Group Leader Fellow, University of Copenhagen, Dept. of Neuroscience and Pharmacology
2005-2011 Post doc, Stanford University, Dept. of Molecular and Cellular Physiology
2002-2005 Post doc, University of Copenhagen, Dept. of Pharmacology
1999-2002 Ph.D., University of Copenhagen, Dept. of Medical Physiology
1994-1998 M.Sc. in Human Biology, University of Copenhagen
1990-1994 B.Sc. in Biology, University of Copenhagen

 
Collaborations within the Center for Synthetic Biology

Dimitrios Stamou
Nikos Hatzakis
Ulrik Gether
Claus Løland

Selected Scientific Publications

Mathiasen, S., Christensen, S.M., Fung, J.J., Rasmussen, S.G.F., Fay, J.F., Jørgensen, S.K., Veshaguri, S., Farrens, D.L., Kiskowski, M., Kobilka, B., Stamou, D. Nanoscale high-content analysis using compositional heterogeneities of single proteoliposomes. Nature Methods 11, 931-934, doi:10.1038/nmeth.3062 (2014).

Pardon, E.Laeremans, T., Triest, S., Rasmussen, S.G.F., Wohlkoenig, A., Ruf, A., Muyldermans, S., Hol, W.G.J., Kobilka, B.K., and Steyaert, J. A general protocol for the generation of Nanobodies for structural biology. Nature Protocols 9, 674-693, doi:10.1038/nprot.2014.039 (2014)

Staus, D. P. Wingler, L.M., Strachan, R.T., Rasmussen, S.G.F., Pardon,E., Ahn,S., Steyaert,J., Kobilka,B.K., Lefkowitz, R.J. 
Regulation of beta(2)-Adrenergic Receptor Function by Conformationally Selective Single-Domain Intrabodies. Molecular Pharmacology 85, 472-481,doi:10.1124/mol.113.089516 (2014)

Irannejad, R., Tomshine, J.C., Tomshine, J.R., Chevalier, M., Mahoney, J.P., Steyaert, J., Rasmussen, S.G.F., Sunahara, R.K., El-Samad, H., Huang, B., von Zastrow, M. Conformational biosensors reveal GPCR signalling from endosomes. Nature 495, 534-538, doi:10.1038/nature12000 (2013). 

Chae, P. S., Rana, R.R., Gotfryd, K., Rasmussen, S.G.F., Kruse, A.C., Cho, K.H., Capaldi, S., Carlsson, E., Kobilka, B., Løland, C.J.Gether, U., Banerjee, S., Byrne, B., Lee, J. K., Gellman, S. H. Glucose-Neopentyl Glycol (GNG) amphiphiles for membrane protein study. Chemical Comm. 49, 2287-2289,  doi:10.1039/c2cc36844g (2013). 

Frandsen, K. H., Rasmussen, K.K., Jensen, M.R., Hammer, K., Pedersen, M., Poulsen, J.-C.N., Arleth, L., and Lo Leggio, L. Binding of the N-Terminal Domain of the Lactococcal Bacteriophage TP901-1 CI Repressor to Its Target DNA: A Crystallography, Small Angle Scattering, and Nuclear Magnetic Resonance Study. Soft Matter 52, 6892-6904,  doi:10.1021/bi400439y (2013). 

Zocher, M., Zhang, C., Rasmussen, S. G. F., Kobilka, B. K. & Mueller, D. J.Cholesterol increases kinetic, energetic, and mechanical stability of the human beta(2)-adrenergic receptor. Proceedings of the National Academy of Sciences of the USA 109, E3463-E3472, doi:10.1073/pnas.1210373109 (2012). 

Chae, P. S., Rasmussen, S.G.F., Rana, R.R., Gotfryd, K., Kruse, A.C., Manglik, A., Cho, K.H., Nurva, S., Gether, U., Guan, L.Løland, C. J., Byrne, B., Kobilka, B. K., Gellman, S. H. A New Class of Amphiphiles Bearing Rigid Hydrophobic Groups for Solubilization and Stabilization of Membrane Proteins. Chemistry-a European Journal 18, 9485-9490,doi:10.1002/chem.201200069 (2012).

Rasmussen S.G.F., DeVree B.T., Zho Y., Kruse A.C., Chung K.Y., Kobilka T.S., Thian F.S., Chae P.S., Pardon E., Calinski D., Mathiesen J.M., Shah S.T.A., Lyons J.A., Caffrey M., Gellman S.H., Steyaert J., Skiniotis G., Weis W.I., Sunahara R.K., Kobilka B.K. Crystal Structure of the β2 Adrenergic Receptor-Gs Protein Complex.
Nature 477:549-555, doi:10.1038/nature10361(2011).

Westfield G., Rasmussen S.G.F., Su M., Dutta S., DeVree B.T., Chung K.Y., Calinski D., Velez-Ruiz G., Oleskie A., Pardon E., Chae P.S., Liu T., Li. S., Woods V.L., Steyeart J., Kobilka B.K., Sunahara R.K., Skiniotis G. Structural flexibility of the Gαs α-helical domain in the β2-adrenoceptor Gs complex.
Proceedings of the National Academy of Sciences USA 108(38):16086-91, doi:10.1073/pnas.1113645108 (2011).

Chung K.Y, Rasmussen S.G.F., Liu T. , Li S., DeVree B.T., Chae P.S., Calinski D., Kobilka B.K., Woods V.L., Sunahara R.K. Conformational changes in the G protein Gs induced by the β2 adrenergic receptor.
Nature 477(7366):611-615, doi:10.1038/nature10488(2011).

Rasmussen S.G.F., Choi H.J., Fung J.J., Casarosa P., Pardon E., Chae P.S., DeVree B.T., Rosenbaum D.M., Kobilka T.S., Thian F.S., Schnapp A., Konetzki I., Sunahara R.K., Gellman S.H., Pautsch A., Steyaert J., Weis W.I., Kobilka B.K. Structure of a Nanobody-Stabilized Active State of the β2 Adrenoceptor.
Nature
469(7329):175-180, doi:10.1038/nature09648(2011).

Chae P.S., Rasmussen S.G.F., Rana R., Gotfryd K., Chandra R., Goren M.A., Kruse A.C., Nurva S., Loland C.J., Pierre Y., Drew D., Popot J.L. Picot D., Fox B.G., Guan L., Gether U., Byrne B., Kobilka B., Gellman S.H. Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nature Methods 7(12):1003-8, doi:10.1038/nmeth.1526(2010).

Yao Y.J., Vélez-Ruiz G., Whorton M.R., Rasmussen S.G.F., DeVree B.T., Deupi X., Sunahara R.K., and Kobilka B.K. The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex.
Proceedings of the National Academy of Sciences USA 106(23):9501-9506, doi:10.1073/pnas.0811437106(2009).

Rasmussen S.G.F., Choi H.J., Rosenbaum D.M., Kobilka T.S., Thian F.S., Edwards P., Burghammer M., Ratnala V.R.P., Sanishvili R., Fischetti R., Schertler G.F.X, Weis W.I., Kobilka B.K. Crystal structure of the human β2 adrenergic G-protein-coupled receptor.
Nature 450:383-387, doi: 10.1038/nature06325(2007).