Claude Sauter
Biography - Claude Sauter
Institute for Molecular and Cellular Biology (IBMC), Architecture and Reactivity of RNA (ARN), University of Strasbourg and CNRS, France
Claude Sauter is a biochemist; he obtained an advanced studies diploma (diplôme d’études approfondies) in molecular biology and a master’s degree in chemistry-biology in 1994, both at the University of Strasbourg. During his studies, he discovered structural biology, which held a special fascination for him. This discipline explores the mechanisms of living organisms at the atomic scale, making it possible to visualise biomolecules in 3D and to observe how they interact, recognise each other and carry out their mission in the cell, by catalysing chemical reactions for example. He decided to train in X-ray crystallography and applied it to the study of the protein production machinery during his thesis, which he defended in 1999. After a postdoctoral stay at the European Molecular Biology Laboratory (EMBL Heidelberg, Germany) where he completed his training in bioinformatics, he was recruited to the French National Centre for Scientific Research (CNRS) in 2002, as a research fellow in the ARN laboratory at IBMC. He obtained his accreditation (habilitation) to supervise research in 2007, and was promoted to research director in 2015.
Dr. Sauter continues his research on the interactions between enzymes and RNA from model organisms, human cells in relation to various pathologies and, more recently, pathogenic organisms, by combining biochemistry, biophysics and structural biology. To facilitate the preparation of samples for crystallographic analyses, he develops new methods of crystallization (in gels, in microfluidic systems) in parallel. For several years, he has been involved in scientific outreach and meetings (e.g. academic crystallisation contest, the French science fair) with secondary school students and the general public to discuss research careers and perspectives.
Project - Towards real time imaging of biocatalysis using novel X-ray sources
01/09/2021 - 30/04/2024
Enzymes are key players of cellular processes. Characterizing their substrate specificity and catalytic mechanism is essential in basic enzymology in order to understand their normal function and their dysfunctions caused by mutations that can subsequently lead to diseases, and consequently be able to design inhibitors in drug discovery or create new catalysts for biotechnological applications in synthetic biology. This project focuses on the application of novel molecular imaging approaches based on time-resolved serial crystallography to visualize an enzyme in action.
These approaches will be applied to follow a key catalytic reaction in protein synthesis, called tRNA aminoacylation. Transfer RNAs (tRNAs) play the role of adapters in the expression of the genetic code, and the decoding of genes composed of four letters (the four nucleotides that constitute DNA) into proteins that are themselves composed of 20 letters (the amino acids). When the cellular protein factory – aka the ribosome – scans a messenger RNA (mRNA), tRNAs recognize groups of three letters in the message – the codons – and fetch the corresponding amino acids, which are then incorporated by the ribosome in the nascent protein chain, following the order specified in the mRNA. Prior to this step, amino acids are bound to their tRNA carriers by a family of enzymes called aminoacyl-tRNA synthetases (aaRSs). There are 20 of these enzymes, one for each amino acid, and their specificity of reaction – i.e. their ability to select the correct couple of amino acid and tRNA – is crucial for the fidelity of protein synthesis.
Since their discovery in the 1960s, these enzymes have been the subject of numerous studies exploring their specificity for substrate recognition, their catalytic mechanism, their evolution and, more recently, their dysfunctions in relation to pathogenic mutations in humans and their potential as drug targets in pathogens. Our mechanistic understanding of the catalysis they perform is based on biochemical and structural analyses, and static atomic pictures or "snapshots" obtained by X-ray crystallography. However, the visualization of the dynamics of these enzyme-substrate systems - local movements at the heart of the catalytic site or at long distance communication between domains or subunits - are crucial aspects for a complete understanding, but they remain unexplored due to the lack of an appropriate experimental approach.
The last decade has seen a major change in biocrystallography with the advent of serial crystallography in connection with the introduction of new X-ray sources: X-ray free electron lasers (XFELs) and fourth-generation synchrotrons. These ultra-intense sources can be used to analyse series of very small crystals with a very short time resolution (milliseconds down to femtoseconds), making it possible to probe molecular systems on these time scales and to observe the rapid dynamics associated with the chemical steps of biological catalysis. This is a formidable and unprecedented opportunity for structural enzymology, since it is now possible to trigger a catalytic reaction on demand and follow its molecular mechanism and associated motions in real time.
The ultimate goal of this project is to apply time-resolved serial crystallography to directly visualize, for the first time, a key reaction in protein synthesis and to create a molecular movie of a complex and essential enzymatic process such as tRNA aminoacylation.
Post-doc biography - Petr Pachl
Institute for Molecular and Cellular Biology (IBMC), Architecture and Reactivity of RNA (ARN), University of Strasbourg and CNRS, France
Petr Pachl is a crystallographer and biochemist. After obtaining a Master's degree in biochemistry and genetics of microorganisms in 2006 (University of Chemistry and Technology Prague, Czech Republic), he become interested in structural biology and rational structure-based drug design. During that period, he received training in crystallography and protein purification. He gained more experience in enzyme kinetics and established many collaborations in protein crystallization field. All of these skills were formalised in his thesis (Institute of Organic Chemistry and Biochemistry (IOCB), Czech Academy of Sciences).
After his PhD defence he accepted a post-doctoral position in the same institute (Pavlína Maloy Řezáčová Group – Structural biology) to deepen his knowledge in protein crystallography and to be part of a core team that maintained the crystallization and data collection facility at IOCB. This included everyday care of several crystallization robots, imagining systems, as well as home source diffraction station, and periodical data collection and data processing at the BESSY synchrotron. It also involved participation in various structural biology projects, including novel drug design, structure of protein-protein and protein-DNA complexes or membrane proteins.
In 2018, Petr Pachl moved to Australia to take up a post-doctoral position at the University of Sydney’s Mackay & Matthews lab to work on LIM-LID protein complexes that was, unfortunately, interrupted prematurely due to the 2020 coronavirus pandemic. He therefore returned to IOCB to continue working on various structural biology projects, mainly aiming for novel drug development and fragment-based screening.
He joined Claude Sauter's research group in April 2022, to continue the work started by Julian Nommé, with the goal of developing new methodologies combining time-resolved serial crystallography with new X-ray sources. The aim of the project will be to directly visualize in the form of a molecular movie, for the very first time, an aspartyl-tRNA synthetase in action during a key step of the enzymatic synthesis.
Post-doc biography - Julian Nommé
Institute for Molecular and Cellular Biology (IBMC), Architecture and Reactivity of RNA (ARN), University of Strasbourg and CNRS, France
Julian Nommé is a biochemist. After obtaining a Master's degree in biochemistry and molecular biology in 2005 (University of La Rochelle, France), he became interested in bioinformatics methods such as molecular modeling and dynamics, which he applied to the design of anti-cancer molecules during his thesis (University of Nantes, France) funded by the Ligue contre le Cancer. During his PhD, he realized that interdisciplinarity and developing skills at the interface between bioinformatics and structural biochemistry would allow him to better understand the biological problems he was studying. He thus decided to train in X-ray crystallography during a 4-year post-doctoral stay in the United States in Arnon Lavie's group (UIC). During this period, he developed many skills ranging from gene cloning to protein structure determination and became passionate about biophysical methods of characterization, crystallization and resolution of three-dimensional structures of macromolecules that he applied to the understanding of biological mechanisms and the development of therapeutic molecules.
After this experience abroad, he moved back to France and integrated Lionel Mourey's group (IPBS, Toulouse). He obtained a research grant from the ARC foundation and set up a project aiming to better understand the biological mechanisms related to the formation of microtubules and develop new anti-cancer molecules. Subsequently, he worked at the Laboratory of Biological Systems and Process Engineering (LISBP, Toulouse), where he brought his skills in biochemistry and structural biology and actively participated in the development of a revolutionary method for recycling plastics by biological means.
He was part of Claude Sauter's research group from September 2021 to March 2022.
Links
- More about Claude Sauter on his Xtal pages and on his team Biology of tRNA and pathogenicity at ARN
- Check out the film Diving into the heart of the molecules of life that follows the different steps of a crystallographic study and describes the work of researchers at ARN
