Xavier Deupi i Corral

Senior scientist
Condensed Matter Theory Group >>
Building/Room: WHGA/123
Paul Scherrer Institute
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Telefon
E-Mail
Research Activities/Specialties
G protein-coupled receptors (GPCRs) are a family of seven transmembrane helix proteins found in almost all eukaryotic organisms, with approximately 800 genes in the human genome. These membrane proteins are essential in cell physiology, as they can be activated by an extraordinary diversity of extracellular signals, such as photons, odorants, protonated amines, peptides or glycoprotein hormones. Activated receptors can then trigger cellular signaling cascades through interaction with intracellular heterotrimeric G proteins and arrestins. As malfunction of GPCRs is commonly translated into pathological outcomes, these proteins constitute one of the most attractive pharmaceutical targets, constituting the target of around 30% of currently marketed drugs.
Despite their physiological and therapeutical importance, our understanding of the ligand-induced molecular mechanisms of GPCR activation is hampered by the relative scarcity of structural data. In the last decade, advances in protein engineering, crystallization methods and X-ray crystallography techniques have allowed the determination of more than 150 crystal structures of 40 different GPCRs in complex with ligands of varied pharmacology, peptides and with other proteins.
In my research I aim to understand how extracellular ligands trigger the process of signal transduction in GPCRs. Using a combination of structural bioinformatics, molecular dynamics and data-mining of structure and sequence databases, I extract as much information as possible from experimentally determined protein structures. This knowledge is used to design new experiments and to build experimentally testable models of GPCR function that will lead to a better understanding of ligand selectivity and efficacy.
I am particularly interested in determine the molecular principles of ligand selectivity (i.e. how specific ligands recognize certain receptors), efficacy (i.e. how ligands activate GPCRs) and biased signaling (i.e. how specific ligands preferentially trigger certain signaling pathways).
Despite their physiological and therapeutical importance, our understanding of the ligand-induced molecular mechanisms of GPCR activation is hampered by the relative scarcity of structural data. In the last decade, advances in protein engineering, crystallization methods and X-ray crystallography techniques have allowed the determination of more than 150 crystal structures of 40 different GPCRs in complex with ligands of varied pharmacology, peptides and with other proteins.
In my research I aim to understand how extracellular ligands trigger the process of signal transduction in GPCRs. Using a combination of structural bioinformatics, molecular dynamics and data-mining of structure and sequence databases, I extract as much information as possible from experimentally determined protein structures. This knowledge is used to design new experiments and to build experimentally testable models of GPCR function that will lead to a better understanding of ligand selectivity and efficacy.
I am particularly interested in determine the molecular principles of ligand selectivity (i.e. how specific ligands recognize certain receptors), efficacy (i.e. how ligands activate GPCRs) and biased signaling (i.e. how specific ligands preferentially trigger certain signaling pathways).
Group members
People | Position | Telephone | |
---|---|---|---|
Dr. Xavier Deupi | Principal Investigator | +41 56 310 3337 | xavier.deupi@psi.ch |
Dr. Pikyee Ma | Postdoctoral researcher | +41 56 310 5295 | pik-yee.ma@psi.ch |
Dr. Ramon Guixa | Postdoctoral researcher | +41 56 310 33 37 | ramon.guixa@psi.ch |
People | Position | Period |
---|---|---|
Dr. Eshita Mutt | Postdoctoral researcher/ PSI-Fellow | 2015 - 2019 |
Dr. Tilman Flock | Postdoctoral researcher / ETH Fellow | 2016-2018 |
Milos Matkovic | PhD. Student | 2013-2016 |
Dr. Chayne Piscitelli | Postdoctoral researcher / ETH Fellow | 2011-2016 |
Dr. Florian Brückner | Postdoctoral researcher / Marie Curie and EMBO Fellow | 2011-2014 |
Publications
2019
- An online resource for GPCR structure determination and analysis
NATURE METHODS , (2019).DOI: 10.1038/s41592-018-0302-x(link is external)
- Arrestin-1 engineering facilitates complex stabilization with native rhodopsin
Scientific Reports 9, 439 (2019).DOI: 10.1038/s41598-018-36881-4(link is external)
- Elucidating the Structure?Activity Relationship of the Pentaglutamic Acid Sequence of Minigastrin with Cholecystokinin Receptor Subtype 2
BIOCONJUGATE CHEMISTRY , (2019).DOI: 10.1021/acs.bioconjchem.8b00849(link is external)
2018
- Convergent evolution of tertiary structure in rhodopsin visual proteins from vertebrates and box jellyfish
Proceedings of the National Academy of Sciences 115, 6201 (2018).DOI: 10.1073/pnas.1721333115(link is external)
- Crystal structure of rhodopsin in complex with a mini-G o sheds light on the principles of G protein selectivity
Science Advances 4, eaat7052 (2018).DOI: 10.1126/sciadv.aat7052(link is external)
- GPCR-SAS: A web application for statistical analyses on G protein-coupled receptors sequences
PLOS ONE 13, e0199843 (2018).DOI: 10.1371/journal.pone.0199843(link is external)
2017
- The DRF motif of CXCR6 as chemokine receptor adaptation to adhesion
PLOS ONE 12, e0173486 (2017).DOI: 10.1371/journal.pone.0173486(link is external)
2016
- Diverse activation pathways in class A GPCRs converge near the G protein-coupling region
Nature 536, 484-487 (2016).DOI: 10.1038/nature19107
- Structural role of the T94I rhodopsin mutation in congenital stationary night blindness
EMBO Rep 17, 1431-1440 (2016).DOI: 10.15252/embr.201642671
- Backbone NMR reveals allosteric signal transduction networks in the beta 1-adrenergic receptor
Nature 530, 237-241 (2016).DOI: 10.1038/nature16577
- SAS-6 engineering reveals interdependence between cartwheel and microtubules in determining centriole architecture
Nat Cell Biol 18, 393-403 (2016).DOI: 10.1038/ncb3329
2015
- Batch crystallization of rhodopsin for structural dynamics using an X-ray free-electron laser
Acta Crystallogr F Struct Biol Commun 71, 856-860 (2015).DOI: 10.1107/S2053230X15009966
- Probing G alpha i1 protein activation at single-amino acid resolution
Nat Struct Mol Biol 22, 686-694 (2015).DOI: 10.1038/nsmb.3070
- A molecular pharmacologist's guide to G protein-coupled receptor crystallography
Mol Pharmacol 88, 536-551 (2015).DOI: 10.1124/mol.115.099663
- TMalphaDB and TMbetaDB: Web servers to study the structural role of sequence motifs in alpha-helix and beta-barrel domains of membrane proteins
BMC Bioinformatics 16, 266 (2015).DOI: 10.1186/s12859-015-0699-5
- Conformational activation of visual rhodopsin in native disc membranes
Sci Signal 8, ra26 (2015).DOI: 10.1126/scisignal.2005646
2014
- Functional map of arrestin-1 at single amino acid resolution
Proc Natl Acad Sci U S A 111, 1825-1830 (2014).DOI: 10.1073/pnas.1319402111
- Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation
Structure 22, 1077-1089 (2014).DOI: 10.1016/j.str.2014.05.010
- Coronin 1 regulates cognition and behavior through modulation of camp/protein kinase a signaling
PLoS Biol 12, e1001820 (2014).DOI: 10.1371/journal.pbio.1001820
- Retinal proteins - you can teach an old dog new tricks
Biochim Biophys Acta 1837, 531-532 (2014).DOI: 10.1016/j.bbabio.2014.02.019
- Relevance of rhodopsin studies for GPCR activation
Biochim Biophys Acta 1837, 674-682 (2014).DOI: 10.1016/j.bbabio.2013.09.002
- Molecular dynamics: a stitch in time
Nat Chem 6, 7-8 (2014).DOI: 10.1038/nchem.1832
2013
- Molecular signatures of G protein-coupled receptors
Nature 494, 185-194 (2013).DOI: 10.1038/nature11896
- Insights into congenital stationary night blindness based on the structure of G90D rhodopsin
EMBO Rep 14, 520-526 (2013).DOI: 10.1038/embor.2013.44
- Relation between sequence and structure in membrane proteins
Bioinformatics 29, 1589-1592 (2013).DOI: 10.1093/bioinformatics/btt249
- Structure of beta-adrenergic receptors
Methods Enzymol 520, 117-151 (2013).DOI: 10.1016/B978-0-12-391861-1.00006-X
2012
- Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy
Proc Natl Acad Sci U S A 109, 6733-6738 (2012).DOI: 10.1073/pnas.1201093109
- Conserved activation pathways in G protein-coupled receptors
Biochem Soc Trans 40, 383-388 (2012).DOI: 10.1042/BST20120001
- Ligands stabilize specific GPCR conformations: But how?
Structure 20, 1289-1290 (2012).DOI: 10.1016/j.str.2012.07.009
- Stabilized G protein binding site in the structure of constitutively active metarhodopsin-ii
Proc Natl Acad Sci U S A 109, 119-124 (2012).DOI: 10.1073/pnas.1114089108
- Quantification of structural distortions in the transmembrane helices of GPCRs
Humana Press Eds.: N Vaidehi and J Klein-Seetharaman) 219-235 (2012).DOI: 10.1007/978-1-62703-023-6_13
2011
- A structural insight into the reorientation of transmembrane domains 3 and 5 during family a G protein-coupled receptor activation
Mol Pharmacol 79, 262-269 (2011).DOI: 10.1124/mol.110.066068
- Molecular basis of ligand dissociation in beta-adrenergic receptors
PLoS One 6, e23815 (2011).DOI: 10.1371/journal.pone.0023815
- Structural insights into agonist-induced activation of G protein-coupled receptors
Curr Opin Struct Biol 21, 541-551 (2011).DOI: 10.1016/j.sbi.2011.06.002
2010
- Tracking G protein-coupled receptor activation using genetically encoded infrared probes
Nature 464, 1386-1389 (2010).DOI: 10.1038/nature08948
- Influence of the g- conformation of Ser and Thr on the structure of transmembrane helices
J Struct Biol 169, 116-123 (2010).DOI: 10.1016/j.jsb.2009.09.009
- Energy landscapes as a tool to integrate GPCR structure, dynamics, and function
Physiology (Bethesda) 25, 293-303 (2010).DOI: 10.1152/physiol.00002.2010
2009
- The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex
Proc Natl Acad Sci U S A 106, 9501-9506 (2009).DOI: 10.1073/pnas.0811437106
- Ligand-regulated oligomerization of beta 2 adrenoceptors in a model lipid bilayer
EMBO J 28, 3315-3328 (2009).DOI: 10.1038/emboj.2009.267
2008
- Characterization of a conformationally sensitive TOAC spin-labeled substance P
Peptides 29, 1919-1929 (2008).DOI: 10.1016/j.peptides.2008.08.002
2007
- The activation mechanism of chemokine receptor CCR5 involves common structural changes but a different network of interhelical interactions relative to rhodopsin
Cell Signal 19, 1446-1456 (2007).DOI: 10.1016/j.cellsig.2007.01.022
- The role of internal water molecules in the structure and function of the rhodopsin family of G protein-coupled receptors
Chembiochem 8, 19-24 (2007).DOI: 10.1002/cbic.200600429
- Conformational complexity of G protein-coupled receptors
Trends Pharmacol Sci 28, 397-406 (2007).DOI: 10.1016/j.tips.2007.06.003
- Charge-charge and cation-pi interactions in ligand binding to G protein-coupled receptors
Theoretical Chemistry Accounts 118, 579-588 (2007).DOI: 10.1007/s00214-007-0341-3
- Activation of G protein-coupled receptors
Adv Protein Chem 74, 137-166 (2007).DOI: 10.1016/S0065-3233(07)74004-4
- Structural models of class a G protein-coupled receptors as a tool for drug design: insights on transmembrane bundle plasticity
Curr Top Med Chem 7, 991-998 (2007).
2006
- Coupling ligand structure to specific conformational switches in the beta 2 adrenoceptor
Nat Chem Biol 2, 417-422 (2006).DOI: 10.1038/nchembio801
- 3D structure of G protein-coupled receptors
Wiley-VCH Verlag GmbH & Co. KGaA 183-203 (2006).DOI: 10.1002/3527608249.ch10
2005
- An activation switch in the rhodopsin family of G protein-coupled receptors: the thyrotropin receptor
J Biol Chem 280, 17135-17141 (2005).DOI: 10.1074/jbc.M414678200
- Probing the beta 2 adrenoceptor binding site with catechol reveals differences in binding and activation by agonists and partial agonists
J Biol Chem 280, 22165-22171 (2005).DOI: 10.1074/jbc.M502352200
- Conformational plasticity of GPCR binding sites
Humana Press (Ed.: LA Devi) 363-386 (2005).
2004
- Ser and Thr residues modulate the conformation of Pro-kinked transmembrane alpha-helices
Biophys J 86, 105-115 (2004).DOI: 10.1016/S0006-3495(04)74088-6
2003
- Activation of CCR5 by chemokines involves an aromatic cluster between transmembrane helices 2 and 3
J Biol Chem 278, 1892-1903 (2003).DOI: 10.1074/jbc.M205685200
2002
- Influence of the environment in the conformation of alpha-helices studied by protein database search and molecular dynamics simulations
Biophys J 82, 3207-3213 (2002).DOI: 10.1016/S0006-3495(02)75663-4
- Design, synthesis and pharmacological evaluation of 5-hydroxytryptamine 1a receptor ligands to explore the three-dimensional structure of the receptor
Mol Pharmacol 62, 15-21 (2002).DOI: 10.1124/mol.62.1.15
2001
- Selective hydrolysis of 2,4-diaminopyrimidine systems: a theoretical and experimental insight into an old rule
J Org Chem 66, 192-199 (2001).DOI: 10.1021/jo0056390
- The TxP motif in the second transmembrane helix of CCR5. A structural determinant of chemokine-induced activation
J Biol Chem 276, 13217-13225 (2001).DOI: 10.1074/jbc.M011670200
2000
- Serine and threonine residues bend alpha-helices in the chi(1) = g- conformation
Biophys J 79, 2754-2760 (2000).DOI: 10.1016/S0006-3495(00)76514-3