Dr. Roger Benoit
Scientist
Forschungsstrasse 111
5232 Villigen PSI
Switzerland
Research Interests
My research focuses on the molecular basis of subtle structural changes that enable biased signaling by G protein-coupled receptors (GPCRs). Recent biophysical evidence suggests that GPCRs, a key family of drug targets, are not merely on/off switches of signal transmission. Rather, the transmission of extracellular signals to the cell interior by GPCRs involves a wide range of dynamic intermediate structural conformations in response to different ligands or drugs (biased signaling). Crystallization of GPCRs is nowadays feasible, but typically requires the investigation of hundreds of constructs and the production milligram amounts of conformationally homogeneous proteins that are stable over a period of several weeks. Stabilized GPCRs embedded in a crystal lattice may not retain all the important subtle conformational changes induced by specific ligands or drugs. Emerging technologies in electron cryo-microscopy (cryo-EM) now provide new possibilities that will in the near future enable structure elucidation of GPCRs from single particles. The key challenge is to engineer GPCR-containing particles that fit the requirements for cryo-EM data collection and analysis. Our understanding of structural rearrangements is complemented by 3D-electron diffraction from crystals or particles, as well as time-resolved X-ray crystallography (Swiss-FEL) experiments. These novel methodologies are expected to unveil new structural details, allowing a deeper understanding of the signaling mechanisms and providing a solid platform for structure-based drug design.
Publications
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Benoit RM
Botulinum neurotoxin diversity from a gene-centered view
Toxins. 2018; 10(8): 310 (14 pp.). https://doi.org/10.3390/toxins10080310
DORA PSI -
Benoit RM, Schärer MA, Wieser MM, Li X, Frey D, Kammerer RA
Crystal structure of the BoNT/A2 receptor-binding domain in complex with the luminal domain of its neuronal receptor SV2C
Scientific Reports. 2017; 7: 43588. https://doi.org/10.1038/srep43588
DORA PSI -
Heydenreich FM, Miljuš T, Jaussi R, Benoit R, Milić D, Veprintsev DB
High-throughput mutagenesis using a two-fragment PCR approach
Scientific Reports. 2017; 7(1): 6787. https://doi.org/10.1038/s41598-017-07010-4
DORA PSI -
Benoit RM, Ostermeier C, Geiser M, Li JSZ, Widmer H, Auer M
Seamless insert-plasmid assembly at high efficiency and low cost
PLoS One. 2016; 11(4): e0153158. https://doi.org/10.1371/journal.pone.0153158
DORA PSI -
Bianchi S, Van Riel WE, Kraatz SHW, Olieric N, Frey D, Katrukha EA, et al.
Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations
Scientific Reports. 2016; 6: 30668. https://doi.org/10.1038/srep30668
DORA PSI -
Christen P, Jaussi R, Benoit R
Biochemie und Molekularbiologie. Eine Einführung in 40 Lerneinheiten
Berlin, Heidelberg: Springer; 2016. https://doi.org/10.1007/978-3-662-46430-4
DORA PSI -
Benoit RM, Frey D, Wieser MM, Thieltges KM, Jaussi R, Capitani G, et al.
Structure of the BoNT/A1 - Receptor complex
Toxicon. 2015; 107: 25-31. https://doi.org/10.1016/j.toxicon.2015.08.002
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 -
Kammerer RA, Benoit RM
Botulinum neurotoxins: New questions arising from structural biology
Trends in Biochemical Sciences. 2014; 39(11): 517-526. https://doi.org/10.1016/j.tibs.2014.08.009
DORA PSI -
Benoit RM, Meisner N-C, Kallen J, Graff P, Hemmig R, Cèbe R, et al.
The X-ray crystal structure of the first RNA recognition motif and site-directed mutagenesis suggest a possible hur redox sensing mechanism
Journal of Molecular Biology. 2010; 397(5): 1231-1244. https://doi.org/10.1016/j.jmb.2010.02.043
DORA PSI -
Meisner N-C, Hintersteiner M, Seifert J-M, Bauer R, Benoit RM, Widmer A, et al.
Terminal adenosyl transferase activity of posttranscriptional regulator HuR revealed by confocal on-bead screening
Journal of Molecular Biology. 2009; 386(2): 435-450. https://doi.org/10.1016/j.jmb.2008.12.020
DORA PSI -
Benoit RM, Wilhelm RN, Scherer-Becker D, Ostermeier C
An improved method for fast, robust, and seamless integration of DNA fragments into multiple plasmids
Protein Expression and Purification. 2006; 45(1): 66-71. https://doi.org/10.1016/j.pep.2005.09.022
DORA PSI