Inhibition of heme piracy using AI designed de novo proteins

To sustain infection in the host, many bacteria express transporters capable of extracting the iron-containing cofactor heme directly from host proteins. I investigated how the transporters ChuA from pathogenic E. coli and HgpC from non-typeable Haemophilus influenzae facilitate this process using a combination of structural modelling, Cryo-EM, X-ray crystallography, mutagenesis, and phenotypic analysis. Based on this understanding, I then utilised AI-based protein design to create binders capable of binding these targets to inhibit their function. Additionally, I further determined the structure of a hemoglobin-nanobody complex, to probe transporter function, and which I further used to help improve these AI models.