G protein-coupled receptors; GPCR signaling complex; Ligand specificity; Subtype localization; Mental disease; signaling; drug design
Sun Dawei, Ostermaier Martin K., Heydenreich Franziska M., Mayer Daniel, Jaussi Rolf, Standfuss Joerg, Veprintsev Dmitry B. (2013), AAscan, PCRdesign and MutantChecker: A Suite of Programs for Primer Design and Sequence Analysis for High-Throughput Scanning Mutagenesis, in PLOS ONE
, 8(10), e78878.
Vishnivetskiy Sergey. A., Ostermaier Martin K., Singhal Ankita, Panneels Valerie, Homan Kristoff T., Glukhova Alisa, Sligar Stephen G., Tesmer John J. G., Schertler Gebhard F. X., Standfuss Joerg, Gurevich Vsevolod V. (2013), Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding, in CELLULAR SIGNALLING
, 25(11), 2155-2162.
Singhal Ankita, Ostermaier Martin K., Vishnivetskiy Sergey A., Panneels Valerie, Homan Kristoff T., Tesmer John J. G., Veprintsev Dmitry, Deupi Xavier, Gurevich Vsevolod V., Schertler Gebhard F. X., Standfuss Joerg (2013), Insights into congenital stationary night blindness based on the structure of G90D rhodopsin, in EMBO REPORTS
, 14(6), 520-526.
Venkatakrishnan Anna J., Deupí Xavier, Lebon Guillaume, Tate Christopher G., Schertler Gebhard FX X, Madan Babu M. (2013), Molecular signatures of G-protein-coupled receptors, in Nature
, 494(7436), 185-194.
Vinothkumar Kutti R, Edwards Patricia C, Standfuss Joerg (2013), Practical aspects in expression and purification of membrane proteins for structural analysis., in Schmidt-Krey Ingeborg (ed.), Humana Press (Springer), NY USA, 17-30.
Maeda Shoji, Schertler Gebhard FX X (2013), Production of GPCR and GPCR complexes for structure determination, in Current Opinion in Structural Biology
, 23(3), 381-392.
Olivella Mireia, Gonzalez Angel, Pardo Leonardo, Deupí Xavier (2013), Relation between sequence and structure in membrane proteins, in Bioinformatics
, 29(13), 1589-1592.
Deupí Xavier (2013), Relevance of rhodopsin studies for GPCR activation, in Biochimica et Biophysica Acta - Bioenergetics
Brueckner Florian, Piscitelli Chayne L., Tsai Chingju, Standfuss Jörg, Deupí Xavier, Schertler Gebhard FX X (2013), Structure of β-adrenergic receptors, in Methods in Enzymology
, 520, 117-151.
Tsai Chingju, Tani Kazutoshi, Irie Katsumasa, Hiroaki Yoko, Shimomura Takushi, McMillan Duncan G G, Cook Gregory M., Schertler Gebhard FX X, Fujiyoshi Yoshinori, Li Xiaodan (2013), Two alternative conformations of a voltage-gated sodium channel, in Journal of Molecular Biology
, 425(22), 4074-4088.
Deupi X, Standfuss J, Schertler G (2012), Conserved activation pathways in G-protein-coupled receptors, in BIOCHEMICAL SOCIETY TRANSACTIONS
, 40, 383-388.
Deupi X, Li XD, Schertler GFX (2012), Ligands Stabilize Specific GPCR Conformations: But How?, in STRUCTURE
, 20(8), 1289-1290.
Deupi Xavier (2012), Quantification of structural distortions in the transmembrane helices of GPCRs., in Vaidehi Nagarajan (ed.), Humana Press (Springer), NY USA, 219-35.
Deupi Xavier, Edwards Patricia, Singhal Ankita, Nickle Benjamin, Oprian Daniel, Schertler Gebhard, Standfuss Jörg (2012), Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II., in Proceedings of the National Academy of Sciences of the United States of America
, 109(1), 119-24.
Stroud Robert M, Schertler Gerhard F X (2011), Membranes., in Current opinion in structural biology
, 21(4), 495-6.
Gonzalez A, Perez-Acle T, Pardo L, Deupi X (2011), Molecular Basis of Ligand Dissociation in beta-Adrenergic Receptors, in PLOS ONE
, 6(9), e23815.
Xie Guifu, D'Antona Aaron M, Edwards Patricia C, Fransen Maikel, Standfuss Jorg, Schertler Gebhard F X, Oprian Daniel D (2011), Preparation of an activated rhodopsin/transducin complex using a constitutively active mutant of rhodopsin., in Biochemistry
, 50(47), 10399-407.
Deupi Xavier, Standfuss Jörg (2011), Structural insights into agonist-induced activation of G-protein-coupled receptors., in Current opinion in structural biology
, 21(4), 541-51.
Ostermaier Mart, Peterhans Christian, Jaussi Rolf, Deupi Xavier, Standfuss Jörg, Functional map of arrestin-1 at single amino acid resolution, in PNAS
Class A GPCRs transduce extracellular signals across the cell membrane by activating cytoplasmic-bound heterotrimeric GTP binding proteins (G proteins), which, in turn, modulate the activity of downstream effector proteins. Despite the physiological and pharmacological relevance of GPCRs, the structural basis of ligand efficacy and receptor activation, and how these elements translate into cytoplasmic trafficking and cellular response still remain elusive.In this research project we will integrate the efforts of several research groups from the Laboratory for Biomolecular Research (Biology and Chemistry Department, Paul Scherrer Institut) of different expertise (structural biology, molecular biology, cellular biology and structural bioinformatics), which will focus on specific subprojects (Figure 1, left). First, we will study ligand binding and how it is translated into selectivity and receptor activation, using beta adrenergic receptors as a model system (subproject A). Second, we will obtain the crystal structure of the rhodopsin-transducin complex, which will serve as a general model for the study of GPCR-G protein complexes, the centerpiece that connects extracellular signals to intracellular effectors (subproject B). Third, we will compare the profile of activated signaling molecules with the dynamic intracellular localization pattern to learn how receptor activation translates into specific patterns of cellular signaling. In this case, we will use the serotonin receptor family as a model system, with the specific goal of integrating the analysis of the serotonergic signaling and trafficking map with the biological function of serotonin in the human central nervous system (subproject C). Combination of the data resulting from the study of different Class A GPCRs will allow us to obtain a global picture of GPCR signaling. Our goal is to link receptor structure, cellular biological data and pharmacological results to physiological function. Thus, our project has significant implications in physiology, pharmacology and therapeutics.