Rasmussen Lab – University of Copenhagen

Søren Rasmussen Lab

The purpose of the research in my lab is to understand how G-protein coupled receptors (GPCRs) and neurotransmitter transporters function at the molecular level.

Group leader

Associate Professor Søren Rasmussen

Department of Neuroscience
Mærsk Tower, room 07-5-77

E-mail: sgfr@sund.ku.dk
Phone: +45 2339 7812

Research Focus

The purpose of the research in my lab is to understand how G-protein coupled receptors (GPCRs) and neurotransmitter transporters function at the molecular level.

Specifically we are interested in
i) neurotransmitter-induced conformational changes in GPCRs and transporters and mechanisms behind their inhibition by antagonists;

ii) how GPCRs activate and discriminate between G protein subtypes;

iii) how GPCR function and trafficking behavior is influenced by the lipid environment and architecture. We are mainly working with the adenosine A2A receptor (A2AR), the α2Aand b2 adrenergic receptors (b2AR), the G proteins through which these signal, and the serotonin transporter (SERT). We study these proteins in their purified state or reconstituted in nanodisc or liposomes using various biophysical techniques (protein crystallography, fluorescence spectroscopy, hydrogen-deuterium exchange mass spectrometry, CryoEM, NMR) and biochemical assays (radioligand binding and signalling assays).

To aid our investigations we have generated a number of camelid single chain antibody fragments (nanobodies) against the b2AR and G proteins and are working on obtaining nanobodies against the A2AR and SERT. These nanobodies work as versatile tools to study the structure and function of these proteins in purified and reconstituted systems as well as in live cultured cells and neurons.

In Parkinson’s disease (PD) long-term use of dopamine-replacing agents is associated with the development of motor complications. Antagonists of A2AR have been reported to reduce functional inhibition of dopamine D2 receptor signaling in the GABAergic neurons in the striatopallidal pathway leading to improvement in motor control of PD patients. We are in the process of developing intracellular binding nanobodies that functionally knockout A2AR signaling with the aim of delivering these by targeted adeno-associated virus to mouse models with motor deficiencies mimicking PD.

Key Publications

  • McMahon C., Baier A.S., Pascolutti R., Wegrecki M., Zheng S., Ong J.X., Erlandson S.C., Hilger D., Rasmussen S.G.F., Ring A.M., Manglik A., Kruse A.C., Yeast surface display platform for rapid discovery of conformationally selective nanobodies.Nature Structural and Molecular Biology (2018), in press
  • Clark L., Dikiy I., Chapman K., Rödström K.E.J., Aramini J., LeVine M.V., Khelashvili G., Rasmussen S.G.F., Gardner K.H., Rosenbaum D.M., Ligand modulation of sidechain dynamics in a wild-type human GPCR, Elife (2017), DOI: https://doi.org/10.7554/eLife.28505
  • DeVree B.T., Mahoney J.P., Vélez-Ruiz G.A., Rasmussen S.G.F, Kuszak A.J., Edwald E., Fung J.J., Manglik A., Masureel M., Du Y., Matt R.A., Pardon E., Steyaert J., Kobilka B.K. and Sunahara R.K., Allosteric coupling from G protein to the agonist binding pocket in GPCRs. Nature (2016) 535:182-6
  • 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 signaling from endosomes. Nature (2013) 495:534-538
  • 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 b2 Adrenergic Receptor-Gs Protein Complex. Nature (2011) 477:550-555. §Authors contributed equally to this work
  • 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. b2 Adrenergic Receptor-Induced conformational changes in the heterotrimeric G protein. Nature (2011) 477: 611-615. §Authors contributed equally to this work
  • 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 an Nanobody-Stabilized Active State of the b2 Adrenoceptor. Nature (2011) 469:175-180. §Authors contributed equally to this work
  • 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 Rearrangements of the Gαs α-Helical Domain in the b2-adrenoceptor Gs Complex. Proc. Natl. Acad. Sci. USA. (2011) 108:16086-91. §Authors contributed equally to this work
  • 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 (2010) 7:1003-8

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