Using AI to design proteins that inhibit bacterial heme-piracy скачать в хорошем качестве

Using AI to design proteins that inhibit bacterial heme-piracy

Speaker: Rhys Grinter Ph.D. Affiliation: Head of Laboratory, The University of Melbourne Covered in this webinar: Learn how bacterial pathogens encode proteins capable of extracting iron-containing cofactors from host proteins. Discover how extraction of iron is crucial as iron is essential for bacterial growth. Learn about Twist clonal genes and AI, assist in screening of haemoglobin binders inhibiting binding to ChuA. Webinar description : Iron, an essential nutrient for most bacteria, is often a limiting nutrient during infection. To obtain the iron required for growth, many bacterial pathogens encode proteins capable of extracting the iron-containing cofactor heme directly from host proteins. Pathogenic Escherichia coli produce the outer membrane transporter ChuA, which binds host hemoglobin and extracts its heme cofactor, before importing heme into the cell. In this work, we utilise a combination of structural modelling, Cryo-EM, X-ray crystallography, mutagenesis, and phenotypic analysis to understand the mechanistic detail of this process. Based on this understanding we utilise artificial intelligence-based protein design to create binders capable of inhibiting E. coli growth by blocking hemoglobin binding to ChuA. Twist Bioscience synthesised clonal genes for 96 of these designs that we rapidly screened, identifying several binders that inhibit E. coli growth at low nanomolar concentrations, without further optimisation. We determine the structure of a subset of these binders, alone and in complex with ChuA, demonstrating that they closely match the computational design. This work demonstrates the utility of de novo-designed proteins for inhibiting bacterial membrane transporters and uses a workflow that could equally be applied to integral membrane proteins in other organisms.