The Good, The Bad, and The Weird of B-Sheet
B-sheets play a pivotal role in protein secondary structure, forming the foundation for diverse supramolecular assemblies. In this presentation, I address questions aimed at understanding B-sheets and their associated supramolecular assemblies.
The Good: Teixobactin, an undecadepsipeptide antibiotic effective against Gram-positive bacteria, disrupts the cell membrane by binding to lipid II and related peptidoglycan precursors. The key question here is, “What is the mechanism of action of teixobactin at the molecular level?” X-ray crystallographic structures of teixobactin derivatives reveal the chemistry of teixobactin, emphasizing the formation of antiparallel B-sheets that create binding sites for anions.
The Bad: In neurodegenerative diseases, amyloidogenic proteins adopt cross-B-sheet amyloid structures with distinct conformations (strains). The first question is, “Can we rapidly identify these amyloid conformations?” Two technologies were developed: (1) EMBER—an imaging method that in situ identifies conformational differences in AB and tau deposits from human brain slices affected by Down syndrome, Alzheimer’s, and Pick’s diseases; (2) TORCH—a de novo designed peptides targeting a specific conformer of a-Synuclein fibril. The second question is, “Can we track the molecular phenotype changes in the micro-environment over the course of amyloid formation?” A multimodalomics technology was introduced: (1) IMAGINE—an in situ multimodal omics methodology enabling the correlation of gene expression levels and metabolite abundances with plaque formation kinetics from a single brain slice.
The Weird: Amyloids and soluble proteins exhibit significant structural differences. The question is, “What structural property differentiates soluble proteins from amyloids?” An energy function was derived to structurally discriminate between amyloids and soluble proteins. Additionally, this energy function identified soluble proteins with high amyloid-like structural characteristics.
Hosted by Professor Sagar Khare
~Coffee/tea will be served prior to the lecture~