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Strukturglykobiologie und Inhibierung der Verankerung von glykosyliertem S-layer über sekundäres Zellwand-Glykopolymer

Project Leader
Schäffer Christina, Project Leader
Duration:
01.01.2023-31.03.2028
Programme:
Einzelprojekte
EU-Project Instruments
Collaborative Project
Type of Research
Basic Research
Project partners
Department of Biochemistry & Microbiology_x000D_ University of Victoria_x000D_ Victoria, BC, V8W 3P6, BC, V8W 3P6 Victoria, Canada.
Contact person: Stephen V. Evans;
Function of the Project Partner: Partner
Sir William Dunn School of Pathology_x000D_ University of Oxford_x000D_ , South Parks Road, OX1 3RE Oxford, United Kingdom.
Contact person: Tanmay Bharat;
Function of the Project Partner: Partner

Further information: https://boku.ac.at/chemie/institut-fuer-biochemie-dchbc/arbeitsgruppe-schaeffer/

Staff
BOKU Research Units
Institute of Biochemistry (DCH/BC)
Institute of Biologisch inspirierte Materialien
Institute of Molecular Modeling and Simulation (MMS)
Funded by
Austrian Science Fund (FWF) , Georg-Coch-Platz 2, 1010 Wien, Austria
Abstract
S-layers are 2D crystalline cell envelope structures of many prokaryotes and are potential targets for therapeutic inhibition. Many S-layers are glycosylated and in Gram-positive bacteria, can be attached through the interaction of an S-layer homology (SLH) domain trimer with peptidoglycan-linked secondary cell wall glycopolymer (SCWP). Current insight in SLH domain trimer-SCWP interactions stems from recombinant, non-glycosylated protein and short, synthetic SCWP fragments. As demonstrated for the model organism Paenibacillus alvei, a terminal pyruvylated N-acetylmannosamine residue of SCWP is essential for binding and two active binding grooves are provided by the SLH domain trimer in a mutually exclusive manner.
Our hypothesis is that the native glycosylation of the P. alvei SLH domain trimer located in the two binding grooves influences the molecular logic of S-layer anchoring to the cell wall. We furthermore hypothesize that the terminal pyruvylated N-acetylmannosamine S-layer binding epitope for SCWP is an ideal starting point to design inhibitors of proper cell wall assembly.
We will analyse the influence of the glycosylation of the SLH domain trimer on binding to SCWP will be studied by analysing its interaction with the SCWP ligand in a bottom-up approach of increasing complexity, in vitro and in vivo. We aim to identify small molecule inhibitors of the SLH domain trimer-SCWP interaction. The project uses chemical synthesis, protein- and glycan-engineering, biophysical protein-carbohydrate interaction analyses, X-ray crystallography, and cryo-electron tomography/ microscopy, and is supported by molecular modelling and simulation.
This interdisciplinary project will yield a detailed mechanistic model of S-layer anchoring in Gram-positives. Understanding the governing glycoprotein-carbohydrate interactions at a molecular level will open avenues for their disruption–a field of increasing importance in the context of bacterial pathogens.

Keywords
Chemical biology; Glycobiology; Structural biology;
Biomolecular simulation; Oligosaccharide synthesis; Protein-Carbohydrate Interaction; Secondary cell wall polymer; S-layer homology domain; Structural biolgy;
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