Title: Structural insights into the mechanism of G protein coupled receptor activation
Speaker: Brian Kobilka, Molecular and Cellular Physiology and Medicine, Beckman Center, Stanford University, CA, U.S.A.
Place: KB3A9 "Lilla hörsalen", KBC

Research Overview
Research in my lab is directed at understanding the structural basis for the functional properties of G protein coupled receptors (GPCRs),which constitute the largest family of membrane proteins in the human genome. GPCRs conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. The beta 2 adrenoceptor (beta2AR) is a prototypical Family A GPCR that mediates physiologic responses to adrenaline and noradrenaline. It regulates the activity of several distinctsignaling pathways through both G protein dependent and G protein independent mechanisms. Like many GPCRs that respond to hormones and neurotransmitters, the beta2AR exhibits modest basal activity in the absence of an agonist. This activity can be modulated by a spectrum of synthetic ligands ranging from inverse agonists, which suppress basal activity, to full agonists. We have obtainedthree-dimensional structures of the beta2AR in inactive and active conformations; and we have used fluorescence spectroscopy and NMR spectroscopy to study the dynamic properties of the receptor, and to map ligand-specificconformational changes. I will discuss what we these studies have taught usabout the structural basis of beta2AR function.

The Company ConfometRX
Structure-based drug discovery for G Protein Coupled Receptors

G protein coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome, and the largest class of targets for drug discovery. Clinical indications for GPCRs include cardiovascular, pulmonary, metabolic and psychiatric disorders, as well as inflammation, cancer and HIV infection.

ConfometRx is developing a platform of structure-based drug discovery technologies to facilitate lead identification and lead optimization for G protein coupled receptors.

This platform includes:
• biophysical technologies for characterizing ligand-induced structural changes in GPCRs
• the generation of GPCR-specific, functional antibodies for target validation, therapeutics and protein crystallography
• the production of pure, functional GPCRs for high-resolution structure determination by crystallographythe economical and efficient labeling of GPCRs with 13C and 15N for NMR spectroscopy studies to characterize receptor-ligand interactions

Publications: Xao, X.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. Proc Natl Acad Sci U S A, 2009. 106(23): p. 9501-9506. Fung, J.J., Deupi, X., Pardo, L., Yao, X.J., Velez-Ruiz, G.A., DeVree, B.,Sunahara, R.K., and Kobilka, B.K.,Ligand regulated oligomerization of beta2-adrenoceptors in a model lipid bilayer.EMBO Journal, 2009. 28(21): p. 3315-28.

Rosenbaum, D.M., Rasmussen, S.G., Kobilka, B.K.The structure and function of G-protein-coupled receptors.Nature, 2009. 459(7245): 356-363.

Bokoch, M.P., Zou, Y., Rasmussen, S.G.F., Liu, C.W., Nygaard, R.,Rosenbaum, D.M., Fung, J.J., Choi, H.J., Thian, F.S., Kobilka, T.S., Puglisi, J.D.,Weis, W.I., Pardo, L., Prosser, R.S., Mueller, L., Kobilka, B.K. Ligand-specific regulation of the extracellular surface of a G proteincoupled receptor. Nature, 2010. 463:p.108-112.

Title: Determinants of sugar-specific gene expression in plants
Sabine Kunz, Department of Plant Physiology, Umeå University
Place: KB3A9 "Lilla hörsalen", KBC

Title: Probing molecular mechanisms regulating trafficking of auxin influx carriers
Lecturer: Ranjan Swarup, University of Nottingham, United Kingdom
Place: KB3A9 "Lilla hörsalen", KBC