Prof. Dr. Gebhard Schertler

Division Head of Biology and Chemistry

Paul Scherrer Institute
Forschungsstrasse 111
5232 Villigen PSI
Switzerland

Secretariat

Francine Weber


Class A G protein-coupled receptor (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 the Laboratory for Biomolecular Research we integrate data from structural biology, molecular biology, cellular biology and structural bioinformatics to study the molecular basis of GPCR function. Specifically, we aim to obtain the crystal structure of the complexes between GPCRs and their cytoplasmic partners, the centerpieces that connect extracellular stimuli to intracellular signals. In addition, we plan to compare the profile of activated signaling molecules with their dynamic intracellular localization pattern to learn how receptor activation translates into specific pathways of cellular signaling. 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.

Isogai S, Deupi X, Opitz C, Heydenreich FM, Tsai CJ, Brueckner F, Schertler GF, Veprintsev DB, Grzesiek S.
Nature.2016;530(7589):237-41.

Molecular signatures of G-protein-coupled receptors(link is external)
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM.
Nature2013;494(7436):185-94

The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor.(link is external)
Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AG, Schertler GF, Tate CG.
Nature.2011;469(7329):241-4.

The structural basis of agonist-induced activation in constitutively active rhodopsin.(link is external)
Standfuss J, Edwards PC, D'Antona A, Fransen M, Xie G, Oprian DD, Schertler GF.
Nature.2011;471(7340):656-60.
  • Ehrenberg D, Varma N, Deupi X, Koyanagi M, Terakita A, Schertler GFX, et al.
    The two-photon reversible reaction of the bistable jumping spider rhodopsin-1
    Biophysical Journal. 2019; 116(7): 1248-1258. https://doi.org/10.1016/j.bpj.2019.02.025
    DORA PSI
  • Haider RS, Wilhelm F, Rizk A, Mutt E, Deupi X, Peterhans C, et al.
    Arrestin-1 engineering facilitates complex stabilization with native rhodopsin
    Scientific Reports. 2019; 9(1): 439 (13 pp.). https://doi.org/10.1038/s41598-018-36881-4
    DORA PSI
  • Mayer D, Damberger FF, Samarasimhareddy M, Feldmueller M, Vuckovic Z, Flock T, et al.
    Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation
    Nature Communications. 2019; 10: 1261 (14 pp.). https://doi.org/10.1038/s41467-019-09204-y
    DORA PSI
  • Nagata T, Koyanagi M, Tsukamoto H, Mutt E, Schertler GFX, Deupi X, et al.
    The counterion–retinylidene Schiff base interaction of an invertebrate rhodopsin rearranges upon light activation
    Communications Biology. 2019; 2: 180 (9 pp.). https://doi.org/10.1038/s42003-019-0409-3
    DORA PSI
  • Tsai C-J, Marino J, Adaixo R, Pamula F, Muehle J, Maeda S, et al.
    Cryo-EM structure of the rhodopsin-Gαi-βγ complex reveals binding of the rhodopsin C-terminal tail to the gβ subunit
    eLife. 2019; 8: e46041 (19 pp.). https://doi.org/10.7554/eLife.46041
    DORA PSI
  • Varma N, Mutt E, Mühle J, Panneels V, Terakita A, Deupi X, et al.
    Crystal structure of jumping spider rhodopsin-1 as a light sensitive GPCR
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2019; 116(29): 14574-14556. https://doi.org/10.1073/pnas.1902192116
    DORA PSI
  • Bhat V, Cogdell R, Crespo-Hernández CE, Datta A, De A, Haacke S, et al.
    Photocrosslinking between nucleic acids and proteins: general discussion
    Faraday Discussions. 2018; 207: 283-306. https://doi.org/10.1039/c8fd90005a
    DORA PSI
  • Chattopadhyay A, Cogdell R, Crespo-Hernández CE, Datta A, De A, Haacke S, et al.
    Light induced charge and energy transport in nucleic acids and proteins: general discussion
    Faraday Discussions. 2018; 207: 153-180. https://doi.org/10.1039/c8fd90004c
    DORA PSI
  • Gerrard E, Mutt E, Nagata T, Koyanagi M, Flock T, Lesca E, et al.
    Convergent evolution of tertiary structure in rhodopsin visual proteins from vertebrates and box jellyfish
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2018; 115(24): 6201-6206. https://doi.org/10.1073/pnas.1721333115
    DORA PSI
  • Koehl A, Hu H, Maeda S, Zhang Y, Qu Q, Paggi JM, et al.
    Structure of the μ–opioid receptor–Gi protein complex
    Nature. 2018; 558(7711): 547-552. https://doi.org/10.1038/s41586-018-0219-7
    DORA PSI
  • Lesca E, Panneels V, Schertler GFX
    The role of water molecules in phototransduction of retinal proteins and G protein-coupled receptors
    Faraday Discussions. 2018; 207: 27-37. https://doi.org/10.1039/c7fd00207f
    DORA PSI
  • Maeda S, Koehl A, Matile H, Hu H, Hilger D, Schertler GFX, et al.
    Development of an antibody fragment that stabilizes GPCR/G-protein complexes
    Nature Communications. 2018; 9(1): 3712 (9 pp.). https://doi.org/10.1038/s41467-018-06002-w
    DORA PSI
  • Mattle D, Kuhn B, Aebi J, Bedoucha M, Kekilli D, Grozinger N, et al.
    Ligand channel in pharmacologically stabilized rhodopsin
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2018; 115(14): 3640-3645. https://doi.org/10.1073/pnas.1718084115
    DORA PSI
  • Nogly P, Weinert T, James D, Carbajo S, Ozerov D, Furrer A, et al.
    Retinal isomerization in bacteriorhodopsin captured by a femtosecond x-ray laser
    Science. 2018; 361(6398): eaat0094 (7 pp.). https://doi.org/10.1126/science.aat0094
    DORA PSI
  • Tsai C-J, Pamula F, Nehmé R, Mühle J, Weinert T, Flock T, et al.
    Crystal structure of rhodopsin in complex with a mini-Go sheds light on the principles of G protein selectivity
    Science Advances. 2018; 4(9): aat7052 (9 pp.). https://doi.org/10.1126/sciadv.aat7052
    DORA PSI
  • Abela R, Beaud P, van Bokhoven JA, Chergui M, Feurer T, Haase J, et al.
    Perspective: opportunities for ultrafast science at SwissFEL
    Structural Dynamics. 2017; 4(6): 61602 (25 pp.). https://doi.org/10.1063/1.4997222
    DORA PSI
  • Haider RS, Rizk A, Schertler GFX, Ostermaier MK
    Comprehensive analysis of the role of arrestin residues in receptor binding
    In: Gurevich VV, ed. The structural basis of arrestin functions. Cham: Springer; 2017. https://doi.org/10.1007/978-3-319-57553-7_7
    DORA PSI
  • Weinert T, Olieric N, Cheng R, Brünle S, James D, Ozerov D, et al.
    Serial millisecond crystallography for routine room-temperature structure determination at synchrotrons
    Nature Communications. 2017; 8(1): 542 (11 pp.). https://doi.org/10.1038/s41467-017-00630-4
    DORA PSI
  • Chakrabarti KS, Agafonov RV, Pontiggia F, Otten R, Higgins MK, Schertler GFX, et al.
    Conformational selection in a protein-protein interaction revealed by dynamic pathway analysis
    Cell Reports. 2016; 14(1): 32-42. https://doi.org/10.1016/j.celrep.2015.12.010
    DORA PSI
  • Isogai S, Deupi X, Opitz C, Heydenreich FM, Tsai C-J, Brueckner F, et al.
    Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor
    Nature. 2016; 530(7589): 237-241. https://doi.org/10.1038/nature16577
    DORA PSI
  • Nango E, Royant A, Kubo M, Nakane T, Wickstrand C, Kimura T, et al.
    A three-dimensional movie of structural changes in bacteriorhodopsin
    Science. 2016; 354(6319): 1552-1557. https://doi.org/10.1126/science.aaH3497
    DORA PSI
  • Nogly P, Panneels V, Nelson G, Gati C, Kimura T, Milne C, et al.
    Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography
    Nature Communications. 2016; 7: 12314 (9 pp.). https://doi.org/10.1038/ncomms12314
    DORA PSI
  • Singhal A, Guo Y, Matkovic M, Schertler G, Deupi X, Yan ECY, et al.
    Structural role of the T94I rhodopsin mutation in congenital stationary night blindness
    EMBO Reports. 2016; 17(10): 1431-1440. https://doi.org/10.15252/embr.201642671
    DORA PSI
  • Venkatakrishnan AJ, Deupi X, Lebon G, Heydenreich FM, Flock T, Miljus T, et al.
    Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region
    Nature. 2016; 536(7617): 484-487. https://doi.org/10.1038/nature19107
    DORA PSI
  • Diaz A, Malkova B, Holler M, Guizar-Sicairos M, Lima E, Panneels V, et al.
    Three-dimensional mass density mapping of cellular ultrastructure by ptychographic X-ray nanotomography
    Journal of Structural Biology. 2015; 192(3): 461-469. https://doi.org/10.1016/j.jsb.2015.10.008
    DORA PSI
  • He X, Robertson N, Jazayeri A, Geroni Gasperina A, Schertler G, Li X
    Large scale expression and purification of the rat 5-HT2c receptor
    Protein Expression and Purification. 2015; 106: 1-9. https://doi.org/10.1016/j.pep.2014.10.010
    DORA PSI
  • Malmerberg E, Bovee-Geurts PHM, Katona G, Deupi X, Arnlund D, Wickstrand C, et al.
    Conformational activation of visual rhodopsin in native disc membranes
    Science Signaling. 2015; 8(367): ra26 (9 pp.). https://doi.org/10.1126/scisignal.2005646
    DORA PSI
  • Neutze R, Brändén G, Schertler GFX
    Membrane protein structural biology using X-ray free electron lasers
    Current Opinion in Structural Biology. 2015; 33: 115-125. https://doi.org/10.1016/j.sbi.2015.08.006
    DORA PSI
  • Nogly P, James D, Wang D, White TA, Zatsepin N, Shilova A, et al.
    Lipidic cubic phase serial millisecond crystallography using synchrotron radiation
    IUCrJ. 2015; 2: 168-176. https://doi.org/10.1107/S2052252514026487
    DORA PSI
  • Panneels V, Wu W, Tsai C-J, Nogly P, Rheinberger J, Jaeger K, et al.
    Time-resolved structural studies with serial crystallography: a new light on retinal proteins
    Structural Dynamics. 2015; 2(4): 041718 (8 pp.). https://doi.org/10.1063/1.4922774
    DORA PSI
  • Schertler GFX
    Rhodopsin on tracks: new ways to go in signaling
    Structure. 2015; 23(4): 606-608. https://doi.org/10.1016/j.str.2015.03.008
    DORA PSI
  • Sun D, Flock T, Deupi X, Maeda S, Matkovic M, Mendieta S, et al.
    Probing Gαi1 protein activation at single-amino acid resolution
    Nature Structural and Molecular Biology. 2015; 22(9): 686-694. https://doi.org/10.1038/nsmb.3070
    DORA PSI
  • Wu W, Nogly P, Rheinberger J, Kick LM, Gati C, Nelson G, et al.
    Batch crystallization of rhodopsin for structural dynamics using an X-ray free-electron laser
    Acta Crystallographica Section F: Structural Biology and Crystallization Communications. 2015; 71: 856-860. https://doi.org/10.1107/S2053230X15009966
    DORA PSI
  • Benoit RM, Frey D, Hilbert M, Kevenaar JT, Wieser MM, Stirnimann CU, et al.
    Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A
    Nature. 2014; 505(7481): 108-111. https://doi.org/10.1038/nature12732
    DORA PSI
  • Frank M, Carlson DB, Hunter MS, Williams GJ, Messerschmidt M, Zatsepin NA, et al.
    Femtosecond X-ray diffraction from two-dimensional protein crystals
    IUCrJ. 2014; 1: 95-100. https://doi.org/10.1107/S2052252514001444
    DORA PSI
  • Heberle J, Deupi X, Schertler G
    Retinal proteins - you can teach an old dog new tricks
    Biochimica et Biophysica Acta: Bioenergetics. 2014; 1837(5): 531-532. https://doi.org/10.1016/j.bbabio.2014.02.019
    DORA PSI
  • Maeda S, Sun D, Singhal A, Foggetta M, Schmid G, Standfuss J, et al.
    Crystallization scale preparation of a stable GPCR signaling complex between constitutively active rhodopsin and G-protein
    PLoS One. 2014; 9(6): e98714 (11 pp.). https://doi.org/10.1371/journal.pone.0098714
    DORA PSI
  • Miller-Gallacher JL, Nehmé R, Warne T, Edwards PC, Schertler GFX, Leslie AGW, et al.
    The 2.1 Å resolution structure of cyanopindolol-bound β1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor
    PLoS One. 2014; 9(3): e92727 (9 pp.). https://doi.org/10.1371/journal.pone.0092727
    DORA PSI
  • Ostermaier MK, Schertler GFX, Standfuss J
    Molecular mechanism of phosphorylation-dependent arrestin activation
    Current Opinion in Structural Biology. 2014; 29: 143-151. https://doi.org/10.1016/j.sbi.2014.07.006
    DORA PSI
  • Pedrini B, Tsai C-J, Capitani G, Padeste C, Hunter MS, Zatsepin NA, et al.
    7 Å resolution in protein two-dimensional-crystal X-ray diffraction at Linac Coherent Light Source
    Philosophical Transactions of the Royal Society B: Biological Sciences. 2014; 369(1647): 20130500 (5 pp.). https://doi.org/10.1098/rstb.2013.0500
    DORA PSI
  • Brueckner F, Piscitelli CL, Tsai C-J, Standfuss J, Deupi X, Schertler GFX
    Structure of β-Adrenergic receptors
    In: Conn PM, ed. G protein coupled receptors. Structure. Methods in enzymology. San Diego: Elsevier; 2013. https://doi.org/10.1016/B978-0-12-391861-1.00006-X
    DORA PSI
  • Maeda S, Schertler GFX
    Production of GPCR and GPCR complexes for structure determination
    Current Opinion in Structural Biology. 2013; 23(3): 381-392. https://doi.org/10.1016/j.sbi.2013.04.006
    DORA PSI
  • Singhal A, Ostermaier MK, Vishnivetskiy SA, Panneels V, Homan KT, Tesmer JJG, et al.
    Insights into congenital stationary night blindness based on the structure of G90D rhodopsin
    EMBO Reports. 2013; 14(6): 520-526. https://doi.org/10.1038/embor.2013.44
    DORA PSI
  • Tsai C-J, Tani K, Irie K, Hiroaki Y, Shimomura T, McMillan DG, et al.
    Two alternative conformations of a voltage-gated sodium channel
    Journal of Molecular Biology. 2013; 425(22): 4074-4088. https://doi.org/10.1016/j.jmb.2013.06.036
    DORA PSI
  • Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM
    Molecular signatures of G-protein-coupled receptors
    Nature. 2013; 494(7436): 185-194. https://doi.org/10.1038/nature11896
    DORA PSI
  • Vishnivetskiy SA, Ostermaier MK, Singhal A, Panneels V, Homan KT, Glukhova A, et al.
    Constitutively active rhodopsin mutants causing night blindness are effectively phosphorylated by GRKs but differ in arrestin-1 binding
    Cellular Signalling. 2013; 25(11): 2155-2162. https://doi.org/10.1016/j.cellsig.2013.07.009
    DORA PSI
  • Deupi X, Standfuss J, Schertler G
    Conserved activation pathways in G-protein-coupled receptors
    Biochemical Society Transactions. 2012; 40(2): 383-388. https://doi.org/10.1042/BST20120001
    DORA PSI
  • Deupi X, Li X-D, Schertler GFX
    Ligands stabilize specific GPCR conformations: but how?
    Structure. 2012; 20(8): 1289-1290. https://doi.org/10.1016/j.str.2012.07.009
    DORA PSI
  • Deupi X, Edwards P, Singhal A, Nickle B, Oprian D, Schertler G, et al.
    Stabilized G protein binding site in the structure of constitutively active metarhodopsin-II
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2012; 109(1): 119-124. https://doi.org/10.1073/pnas.1114089108
    DORA PSI
  • Abrahams J-P, Apweiler R, Balling R, Bertero MG, Bujnicki JM, Chayen NE, et al.
    "4D Biology for health and disease" workshop report
    New Biotechnology. 2011; 28(4): 291-293. https://doi.org/10.1016/j.nbt.2010.10.003
    DORA PSI
  • Moukhametzianov R, Warne T, Edwards PC, Serrano-Vega MJ, Leslie AGW, Tate CG, et al.
    Two distinct conformations of helix 6 observed in antagonist-bound structures of a β1-adrenergic receptor
    Proceedings of the National Academy of Sciences of the United States of America PNAS. 2011; 108(20): 8228-8232. https://doi.org/10.1073/pnas.1100185108
    DORA PSI
  • Standfuss J, Edwards PC, D'Antona A, Fransen M, Xie G, Oprian DD, et al.
    The structural basis of agonist-induced activation in constitutively active rhodopsin
    Nature. 2011; 471(7340): 656-660. https://doi.org/10.1038/nature09795
    DORA PSI
  • Stroud RM, Schertler GFX
    Membranes
    Current Opinion in Structural Biology. 2011; 21(4): 495-496. https://doi.org/10.1016/j.sbi.2011.08.001
    DORA PSI
  • Tarttelin EE, Fransen MP, Edwards PC, Hankins MW, Schertler GFX, Vogel R, et al.
    Adaptation of pineal expressed teleost exo-rod opsin to non-image forming photoreception through enhanced Meta II decay
    Cellular and Molecular Life Sciences. 2011; 68(22): 3713-3723. https://doi.org/10.1007/s00018-011-0665-y
    DORA PSI
  • Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AGW, et al.
    The structural basis for agonist and partial agonist action on a β1-adrenergic receptor
    Nature. 2011; 469(7329): 241-244. https://doi.org/10.1038/nature09746
    DORA PSI
  • Xie G, D'Antona AM, Edwards PC, Fransen M, Standfuss J, Schertler GFX, et al.
    Preparation of an activated rhodopsin/transducin complex using a constitutively active mutant of rhodopsin
    Biochemistry. 2011; 50(47): 10399-10407. https://doi.org/10.1021/bi201126r
    DORA PSI
  • Wuster A, Venkatakrishnan AJ, Schertler GFX, Babu MM
    Spial: analysis of subtype-specific features in multiple sequence alignments of proteins
    Bioinformatics. 2010; 26(22): 2906-2907. https://doi.org/10.1093/bioinformatics/btq552
    DORA PSI
  • Ye S, Zaitseva E, Caltabiano G, Schertler GFX, Sakmar TP, Deupi X, et al.
    Tracking G-protein-coupled receptor activation using genetically encoded infrared probes
    Nature. 2010; 464(7293): 1386-1389. https://doi.org/10.1038/nature08948
    DORA PSI