free electron lasers; Subtype selectivity; serial femtosecond crystallography; G protein-coupled receptors; SwissFEL; GPCR signaling complex; Ligand specificity
Tsai Ching-Ju, Marino Jacopo, Adaixo Ricardo, Pamula Filip, Muehle Jonas, Maeda Shoji, Flock Tilman, Taylor Nicholas MI, Mohammed Inayatulla, Matile Hugues, Dawson Roger JP, Deupi Xavier, Stahlberg Henning, Schertler Gebhard (2019), Cryo-EM structure of the rhodopsin-Gαi-βγ complex reveals binding of the rhodopsin C-terminal tail to the gβ subunit, in
eLife, 8, 1-19.
Tsai Ching-Ju, Pamula Filip, Nehmé Rony, Mühle Jonas, Weinert Tobias, Flock Tilman, Nogly Przemyslaw, Edwards Patricia C., Carpenter Byron, Gruhl Thomas, Ma Pikyee, Deupi Xavier, Standfuss Jörg, Tate Christopher G., Schertler Gebhard F. X. (2018), Crystal structure of rhodopsin in complex with a mini-G o sheds light on the principles of G protein selectivity, in
Science Advances, 4(9), eaat7052-eaat7052.
Nogly Przemyslaw, Weinert Tobias, James Daniel, Carbajo Sergio, Ozerov Dmitry, Furrer Antonia, Gashi Dardan, Borin Veniamin, Skopintsev Petr, Jaeger Kathrin, Nass Karol, Båth Petra, Bosman Robert, Koglin Jason, Seaberg Matthew, Lane Thomas, Kekilli Demet, Brünle Steffen, Tanaka Tomoyuki, Wu Wenting, Milne Christopher, White Thomas, Barty Anton, Weierstall Uwe, et al. (2018), Retinal isomerization in bacteriorhodopsin captured by a femtosecond x-ray laser, in
Science, eaat0094-eaat0094.
Mattle Daniel, Kuhn Bernd, Aebi Johannes, Bedoucha Marc, Kekilli Demet, Grozinger Nathalie, Alker Andre, Rudolph Markus G., Schmid Georg, Schertler Gebhard F. X., Hennig Michael, Standfuss Jörg, Dawson Roger J. P. (2018), Ligand channel in pharmacologically stabilized rhodopsin, in
Proceedings of the National Academy of Sciences, 115(14), 3640-3645.
Nango Eriko, Royant Antoine, Kubo Minoru, Nakane Takanori, Wickstrand Cecilia, Kimura Tetsunari, Tanaka Tomoyuki, Tono Kensuke, Song Changyong, Tanaka Rie, Arima Toshi, Yamashita Ayumi, Kobayashi Jun, Hosaka Toshiaki, Mizohata Eiichi, Nogly Przemyslaw, Sugahara Michihiro, Nam Daewoong, Nomura Takashi, Shimamura Tatsuro, Im Dohyun, Fujiwara Takaaki, Yamanaka Yasuaki, Jeon Byeonghyun, et al. (2016), A three-dimensional movie of structural changes in bacteriorhodopsin, in
Science, 354(6319), 1552-1557.
Singhal Ankita, Guo Ying, Matkovic Milos, Schertler Gebhard, Deupi Xavier, Yan Elsa CY, Standfuss Joerg (2016), Structural role of the T94I rhodopsin mutation in congenital stationary night blindness, in
EMBO reports, 17(10), 1431-1440.
Nogly Przemyslaw, Panneels Valerie, Nelson Garrett, Gati Cornelius, Kimura Tetsunari, Milne Christopher, Milathianaki Despina, Kubo Minoru, Wu Wenting, Conrad Chelsie, Coe Jesse, Bean Richard, Zhao Yun, Båth Petra, Dods Robert, Harimoorthy Rajiv, Beyerlein Kenneth R., Rheinberger Jan, James Daniel, DePonte Daniel, Li Chufeng, Sala Leonardo, Williams Garth J., Hunter Mark S., et al. (2016), Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography, in
Nature Communications, 7, 12314-12314.
Venkatakrishnan A. J., Deupi Xavier, Lebon Guillaume, Heydenreich Franziska M., Flock Tilman, Miljus Tamara, Balaji Santhanam, Bouvier Michel, Veprintsev Dmitry B., Tate Christopher G., Schertler Gebhard F. X., Babu M. Madan (2016), Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region, in
Nature, 536(7617), 484-487.
Neutze Richard, Brändén Gisela, Schertler Gebhard FX (2015), Membrane protein structural biology using X-ray free electron lasers, in
Current Opinion in Structural Biology, 33, 115-125.
Rheinberger Jan, Kick Leonhard M., Nelson Garrett, Deupi Xavier, Standfuss Jörg, Schertler Gebhard, Panneels Valérie, Wu Wenting, Nogly Przemyslaw, Gati Cornelius (2015), Batch crystallization of rhodopsin for structural dynamics using an X-ray free-electron laser, in
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Panneels Valérie, Wu Wenting, Tsai Ching-Ju, Nogly Przemek, Rheinberger Jan, Jaeger Kathrin, Cicchetti Gregor, Gati Cornelius, Kick Leonhard M., Sala Leonardo, Capitani Guido, Milne Chris, Padeste Celestino, Pedrini Bill, Li Xiao-Dan, Standfuss Jörg, Abela Rafael, Schertler Gebhard (2015), Time-resolved structural studies with serial crystallography: A new light on retinal proteins, in
Structural Dynamics, 2(4), 041718-041718.
Nogly Przemyslaw, James Daniel, Wang Dingjie, White Thomas A., Zatsepin Nadia, Shilova Anastasya, Nelson Garrett, Liu Haiguang, Johansson Linda, Heymann Michael, Jaeger Kathrin, Metz Markus, Wickstrand Cecilia, Wu Wenting, Båth Petra, Berntsen Peter, Oberthuer Dominik, Panneels Valerie, Chapman Henry, Cherezov Vadim, Schertler Gebhard, Neutze Richard, Spence John, Moraes Isabel, et al. (2015), Lipidic cubic phase serial millisecond crystallography using synchrotron radiation, in
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Ostermaier Martin K, Schertler Gebhard FX, Standfuss Joerg (2014), Molecular mechanism of phosphorylation-dependent arrestin activation, in
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NATURE COMMUNICATIONS , 8.
G protein-coupled receptors (GPCRs) comprise 2-3% of human proteins and are key for cellular communication in higher organisms. These membrane receptors operate by ligand-dependent coupling to several intracellular effector proteins, including G proteins, kinases and arrestins. GPCR signaling is often modulated by a series of closely related receptors that vary in their relative affinity to natural ligands and pharmaceutical drugs. Cross-reactivity between such related receptors is a common cause of side effects, which reduces the benefits of many medical drugs.The goal of this project is to gain a better understanding of the molecular basis of ligand selectivity in serotonin and adrenergic receptors, both members of the amine family of GPCRs. My group has a long experience in the structure determination of GPCRs, in particular rhodopsin and the ß1 and ß2 adrenergic receptors. Here we propose to target all nine adrenergic receptor subtypes to obtain a set as complete as possible of human GPCR subtypes. The structure of the related amine receptor 5-HTc will provide further templates to study GPCR ligand selectivity. For instance, the antipsychotic drug risperidone binds both adrenergic as well as serotonin receptors with high affinity. Thus, crystal structures of several amine receptor subtypes bound to this inverse agonist may provide important clues on how to prevent drug cross-reactivity.In addition, a deeper understanding of the molecular mechanisms of GPCR activation requires structural knowledge of the complexes between the receptors and their effector molecules. This proposal also aims to solve the structure of the complex between the GPCR rhodopsin, responsible for vision in dim-light conditions, and the Gt and Gi proteins.The recent development of serial femtosecond nanocrystallography using free electron lasers has opened the door for high-throughput structure determination of closely related proteins or protein-ligand complexes. The use of lipidic cubic phases for crystal growth and delivery significantly reduces the amount of protein needed for such experiments. Importantly, data collection using highly brilliant femtosecond laser pulses allows to outrun radiation damage and determine membrane protein structures at previously unprecedented resolution. GPCRs bound to many different pharmacologically important ligands, and in complex with G proteins, are the ideal targets to establish serial femtosecond nanocrystallography for membrane proteins in Switzerland. This project will therefore allow us to be fully prepared for a new user community when the X-ray laser SwissFEL becomes operational at the Paul Scherrer Institute.