InstructFeaturing expert speakers from Instruct Centres across Europe, Instruct-ERIC Webinar Series: Structure Meets Function highlights some of the latest developments in structural biology, demonstrating how integrative methods are enabling scientists to decipher the mechanisms that underpin health and disease.
Watch the previous webinars in the series here.
The third webinar in the series will be hosted by Instruct Centre NL on 13 October 2020, 11:00 - 12:30 CEST.
Webinar moderator: Prof Anastassis Perrakis
Netherlands Cancer Institute, Utrecht University, Oncode Institute
Talk 1: Protein structure and interactions control contacts in the nervous system
Speaker: Bert Janssen
Abstract: Protein-mediated communication and interactions between cells controls the formation, function and pathology of tissues and organs. In our nervous system, at synapses and myelinated axons, two adhesion and signaling protein families, MAG and Teneurins, contribute to basic brain function such as learning and memory formation. The mechanisms by which MAG signals in the axon-myelin interface and Teneurin forms dimers in the synapse are unresolved. We used a hybrid approach of protein crystallography and cryo-EM to resolve protein structures, biophysical methods to determine protein interactions, and cellular assays to unify mechanistic and functional insights and show how MAG and Teneurin protein structure and interactions control intercellular signaling and adhesion.
Talk 2: High-Resolution NMR of antibiotics in the native state
Speaker: Markus Weingarth
Abstract: The rapid rise of antimicrobial resistance (AMR) urgently calls for next-generation antibiotics that use novel modes of actions and that are refractory to AMR development. An ideal candidate could be teixobactin (Ling et al. Nature, 2015), a first of a new class of antibiotics that has generated tremendous interest. Heralded as a gamechanger drug, teixobactin kills a broad spectrum of pathogenic bacteria without detectable resistance. Unfortunately, the hunt for better teixobactin analogues is based on chance discovery because the binding mode is poorly understood. While it is known that teixobactin blocks the cell wall synthesis by targeting the membrane-embedded Lipid II, structural data are virtually absent and were all acquired in unphysiological media such as micelles.
Using a pioneering ultra-sensitive solid-state NMR approach, here we succeeded to resolve the mode of action of teixobactin directly in native bacterial cell membranes (Shukla et al., Nature Communications 2020). Our study reveals an alternative killing mechanism in which teixobactins sequester the target Lipid II molecules in micron-sized clusters on membranes surfaces. Our results explain the excellent bactericidal activity of teixobactin and provide crucial information on its mode of action for the development of better analogues.
Talk 3: Cryo-EM structures reveal the selection process for DNA mismatch repair initiation
Speaker: Meindert Lamers
Abstract: DNA mismatch repair detects and removes mismatches from DNA by a conserved mechanism, reducing the error rate of DNA replication a 100-1000 fold. In this process, MutS homologs scan DNA, recognize mismatches and initiate repair. How the MutS homologs selectively license repair of a mismatch among millions of matched base pairs is not understood. Here we present four cryo-EM structures of E. coli MutS that provide snapshots from scanning homoduplex DNA, to mismatch binding and MutL activation, via an intermediate state. During scanning the homoduplex DNA forms a steric block that prevents MutS from transitioning into the MutL-bound clamp-state, which can only be overcome through kinking of the DNA at a mismatch. Together, these structures reveal how a small conformational change from the homoduplex to heteroduplex-bound MutS acts as a licensing step that triggers a dramatic conformational change that enables MutL binding and initiation of the repair cascade.
