Dr. Jörg Standfuss

Group Leader
Forschungsstrasse 111
5232 Villigen PSI
Suisse
Research Interests
One of the major promises of X-ray free-electron laser (XFEL) technology is to advance structural biology from the determination of molecular snapshots to molecular movies. Together structural and dynamic information provides unique insights into the function of proteins as principal building blocks of our biology.
The key advantage of XFEL-based over conventional diffraction strategies stems from the characteristics of the XFEL pulses, which contain ~1012 X-ray photons but are only tens of femtoseconds long. This fluence is sufficient to produce high-resolution diffraction patterns from very small crystals, while at the same time outrunning most radiation damage processes. The ultrafast XFEL pulses further open up the possibility for time-resolved pump probe experiments on femtosecond to millisecond timescales. Together these advantages allow studying protein structural dynamics at unprecedented spatial and temporal resolution; essentially opening a new frontier in structural biology.
My group focuses on the implementation of time-resolved serial crystallography at the Swiss Light Source (SLS) and the Swiss Free Electron Laser (SwissFEL). Naturally light-sensitive retinal-binding proteins like bacteriorhodopsin are paving the way for time-resolved studies using XFELs. In the near future, we will further see the molecular details of how protons, chloride and sodium ions are pumped across biological membranes by light. My research further aims to answer the question of how protein interactions guide the high quantum efficiency and stereo selectivity of the ultrafast retinal isomerization. Time-resolved crystallography will help us understand fundamental biological processes including the high photo efficiency of the visual sense and how retinal proteins might be improved to better manipulate neural cells in the field of optogenetics.
Laser light allows unmatched precision which makes it an ideal trigger for time-resolved measurements. Learning from biology, chemists have developed a large repertoire of synthetic photoswitches with highly tunable properties. Like their natural counterpart retinal, these chromophores can be inserted into proteins to put them under optical control. In photopharmacological applications reversibly binding ligands are envisioned to precisely control pharmaceutical targets such as ion channels, GPCRs or microtubules. Compared to optogenetics the approach has a wider range of applications including medical intervention in humans since the method relies on the chemical manipulation of native proteins and is not dependent on genetic manipulation. Harnessing the chemistry of such synthetic photoswitches to study proteins that cannot be natively activated by light will dramatically increase the number of biological systems whose structural dynamics can be studied at modern XFEL sources. Dynamic information on how ligands influence a particular protein conformation will provide a crucial new dimension to molecular pharmacology.
Group Members
Group Leader
Technician
Ph.D student
SwissFEL technician
Ph.D student
Ph.D student
News & Events
Jul 2019, Muotatal and Hölloch Exploration

Jul 2019, Time-resolved crystallography now possible at the SLS
https://www.psi.ch/en/media/our-research/molecular-energy-machine-as-a-movie-star
Oct 2018, Climbing at high wire park Pilatus

Jun 2018, Our research featured by the SLAC National Accelerator Laboratory
https://www6.slac.stanford.edu/news/2018-06-14-scientists-make-first-molecular-movie-one-nature%E2%80%99s-most-widely-used-light-sensors
Nov 2017, Przemek Nogly started group at the ETH Zurich on a SNSF Ambizione grant. Congratulations well deserved!!

Sep 2017, Demet Kekilli and Steffen Brünle joined the PSI-FELLOW-II programme co-funded by Horizon2020 of the European Commission

Jan 2017, Our research featured by the Swiss National Science Foundation

http://www.snf.ch/en/researchinFocus/newsroom/Pages/news-170103-press-releases-photosynthesis-on-film-for-the-first-time.aspx
Dec 2016, Chäsfondue and Hotpot Event

Aug 2016, PSI Press Release "Catching Proteins in the Act"
https://www.psi.ch/media/catching-proteins-in-the-act
Jul 2016, Besserstein Hike

Former Members
Publications since 2010
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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
DORA PSI -
Jaeger K, Bruenle S, Weinert T, Guba W, Muehle J, Miyazaki T, et al.
Structural basis for allosteric ligand recognition in the human CC chemokine receptor 7
Cell. 2019; 178(5): 1222-1230. https://doi.org/10.1016/j.cell.2019.07.028
DORA PSI -
James D, Weinert T, Skopintsev P, Furrer A, Gashi D, Tanaka T, et al.
Improving high viscosity extrusion of microcrystals for time-resolved serial femtosecond crystallography at X-ray lasers
Journal of Visualized Experiments. 2019;(144): e59087. https://doi.org/10.3791/59087
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 -
Standfuss J
Membrane protein dynamics studied by X-ray lasers - or why only time will tell
Current Opinion in Structural Biology. 2019; 57: 63-71. https://doi.org/10.1016/j.sbi.2019.02.001
DORA PSI -
Weinert T, Skopintsev P, James D, Dworkowski F, Panepucci E, Kekilli D, et al.
Proton uptake mechanism in bacteriorhodopsin captured by serial synchrotron crystallography
Science. 2019; 365(6448): 61-65. https://doi.org/10.1126/science.aaw8634
DORA PSI -
Wickstrand C, Nogly P, Nango E, Iwata S, Standfuss J, Neutze R
Bacteriorhodopsin: structural insights revealed using X-ray lasers and synchrotron radiation
Annual Review of Biochemistry. 2019; 88: 59-83. https://doi.org/10.1146/annurev-biochem-013118-111327
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 -
Standfuss J, Spence J
Serial crystallography at synchrotrons and X-ray lasers
IUCrJ. 2017; 4: 100-101. https://doi.org/10.1107/S2052252517001877
DORA PSI -
Tsai C-J, Standfuss J
Structural biology: signalling under the microscope
Nature. 2017; 546(7656): 36-37. https://doi.org/10.1038/nature22491
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 -
Jaeger K, Dworkowski F, Nogly P, Milne C, Wang M, Standfuss J
Serial millisecond crystallography of membrane proteins
In: Moraes I, ed. The next generation in membrane protein structure determination. Advances in experimental medicine and biology. Cham: Springer; 2016:137-149. https://doi.org/10.1007/978-3-319-35072-1_10
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 -
Peterhans C, Lally CCM, Ostermaier MK, Sommer ME, Standfuss J
Functional map of arrestin binding to phosphorylated opsin, with and without agonist
Scientific Reports. 2016; 6: 28686 (14 pp.). https://doi.org/10.1038/srep28686
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 -
Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, et al.
Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser
Nature. 2015; 523: 561-567. https://doi.org/10.1038/nature14656
DORA PSI -
Mattle D, Singhal A, Schmid G, Dawson R, Standfuss J
Mammalian expression, purification, and crystallization of rhodopsin variants
In: Jastrzebska B, ed. Rhodopsin. Methods and protocols. Methods in molecular biology. New York: Humana Press; 2015:39-54. https://doi.org/10.1007/978-1-4939-2330-4_3
DORA PSI -
Nogly P, Standfuss J
Light-driven Na+ pumps as next-generation inhibitory optogenetic tools
Nature Structural and Molecular Biology. 2015; 22(5): 351-353. https://doi.org/10.1038/nsmb.3017
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 -
Standfuss J
Viral chemokine mimicry. How do viruses trick the human immune system?
Science. 2015; 347(6226): 1071-1072. https://doi.org/10.1126/science.aaa7998
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 -
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 -
Ostermaier MK, Peterhans C, Jaussi R, Deupi X, Standfuss J
Functional map of arrestin-1 at single amino acid resolution
Proceedings of the National Academy of Sciences of the United States of America PNAS. 2014; 111(5): 1825-1830. https://doi.org/10.1073/pnas.1319402111
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 -
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
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 -
Sun D, Ostermaier MK, Heydenreich FM, Mayer D, Jaussi R, Standfuss J, et al.
AAscan, PCRdesign and MutantChecker: a suite of programs for primer design and sequence analysis for high-throughput scanning mutagenesis.
PLoS One. 2013; 8(10): e78878 (9 pp.). https://doi.org/10.1371/journal.pone.0078878
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, 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 -
Deupi X, Standfuss J
Structural insights into agonist-induced activation of G-protein-coupled receptors
Current Opinion in Structural Biology. 2011; 21(4): 541-551. https://doi.org/10.1016/j.sbi.2011.06.002
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 -
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