Towards determination of crystal structures of proteins factors involved in infectious diseases, human diseases, and essential biological pathways

This proposal aims at determining the crystallographic structures of proteins involved in human disease in order to gain a deep understanding of related biological systems and find pharmacological targets for novel therapy development. The latter includes virulence factors from Mycobacterium tuberculosis (Mtb), the cause of human tuberculosis, to mycobacteriophage endolysins with potential antimicrobial application, secreted Mtb proteins that inhibit the host innate immune responses, multitargeting essential proteins involved in peptidoglycan synthesis, as well as proteins associated with cancer. In this line, this proposal intends to carry out the structural and functional characterization of: 1) components of the ESX-5 secretion system, a pivotal virulence factor in Mtb and potential pharmacological target; 2) LysA endolysins produced by D29 and DS6A mycobacteriophages with potential application as enzybiotics specifically targeting infections caused by pathogenic mycobacteria; 3) Mur ligases from Mtb and other ESKAPE pathogens, which synthetise peptidoglycan layer precursors and are essential in bacteria; 4) PknG, a Mtb Ser/Thr kinase that is secreted to the macrophages cytoplasm and inhibits the innate immune responses, allowing Mtb survival inside macrophages; 5) AGT, a peroxisomal PLP-dependent enzyme essential for glyoxylate detoxification, whose loss of function causes primary hyperoxaluria type I; 6) Fascin1, an actin-binding protein essential for the packaging and stabilization of actin bundles, is involved in cell migration and invasion, and expressed in most metastatic cancers; and 7) Cyanobacterial essential photoreceptor OCP and its photoprotective partner FRP.