Prof. Dr. Gebhard Schertler

Division Head of Biology and Chemistry
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Secretariat
Group Research
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.
Representative publications
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.
Publications
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Avsar SY, Kapinos LE, Schoenenberger C-A, Schertler GFX, Mühle J, Meger B, et al.
Immobilization of arrestin-3 on different biosensor platforms for evaluating GPCR binding
Physical Chemistry Chemical Physics. 2020; 22(41): 24086-24096. https://doi.org/10.1039/d0cp01464h
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Henzi A, Senatore A, Lakkaraju AKK, Scheckel C, Mühle J, Reimann R, et al.
Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice
PLoS One. 2020; 15(11): e0242137 (22 pp.). https://doi.org/10.1371/journal.pone.0242137
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Karathanou K, Lazaratos M, Bertalan É, Siemers M, Buzar K, Schertler GFX, et al.
A graph-based approach identifies dynamic H-bond communication networks in spike protein S of SARS-CoV-2
Journal of Structural Biology. 2020; 212(2): 107617 (19 pp.). https://doi.org/10.1016/j.jsb.2020.107617
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Nass K, Cheng R, Vera L, Mozzanica A, Redford S, Ozerov D, et al.
Advances in long-wavelength native phasing at X-ray free-electron lasers
IUCrJ. 2020; 7: 965-975. https://doi.org/10.1107/S2052252520011379
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Rößler P, Mayer D, Tsai C-J, Veprintsev DB, Schertler GFX, Gossert AD
GPCR activation states induced by nanobodies and mini-G proteins compared by NMR spectroscopy
Molecules. 2020; 25(24): 5984 (17 pp.). https://doi.org/10.3390/molecules25245984
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Skopintsev P, Ehrenberg D, Weinert T, James D, Kar RK, Johnson PJM, et al.
Femtosecond-to-millisecond structural changes in a light-driven sodium pump
Nature. 2020; 583: 314-318. https://doi.org/10.1038/s41586-020-2307-8
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Spillmann M, Thurner L, Romantini N, Zimmermann M, Meger B, Behe M, et al.
New insights into arrestin recruitment to GPCRs
International Journal of Molecular Sciences. 2020; 21(14): 4949 (14 pp.). https://doi.org/10.3390/ijms21144949
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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; 2017:83-102. https://doi.org/10.1007/978-3-319-57553-7_7
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Heifetz A, Schertler GFX, Seifert R, Tate CG, Sexton PM, Gurevich VV, et al.
GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014
Naunyn-Schmiedeberg's Archives of Pharmacology. 2015; 388(8): 883-903. https://doi.org/10.1007/s00210-015-1111-8
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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; 2013:117-151. https://doi.org/10.1016/B978-0-12-391861-1.00006-X
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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