The hypothetical periplasmic protein PA1624 fromPseudomonas aeruginosafolds into a unique two-domain structure

Abstract

The crystal structure of the 268-residue periplasmic protein PA1624 from the opportunistic pathogen Pseudomonas aeruginosa PAO1 was determined to high resolution using the Se-SAD method for initial phasing. The protein was found to be monomeric and the structure consists of two domains, domains 1 and 2, comprising residues 24–184 and 185–268, respectively. The fold of these domains could not be predicted even using state-of-the-art prediction methods, and similarity searches revealed only a very distant homology to known structures, namely to Mog1p/PsbP-like and OmpA-like proteins for the N- and C-terminal domains, respectively. Since PA1624 is only present in an important human pathogen, its unique structure and periplasmic location render it a potential drug target. Consequently, the results presented here may open new avenues for the discovery and design of antibacterial drugs.

Unsupervised Machine Learning Organization of the Functional Dark Proteome of Gram-Negative “Superbugs”: Six Protein Clusters Amenable for Distinct Scientific Applications

“…Finally, Cluster 6 (17.4% of all HPs) mainly contains conserved, acidic proteins with relatively larger sizes, low disordered content, and high PDB coverage, and many are coded by genes included in operons. Remarkably, this cluster contains the drug target candidate PA1624, whose inter-homodimer druggable interface has been previously suggested as a potential antimicrobial target . The cluster is enriched in exposed proteins, and its centroid is the closest one to control virulence factors and antigens.…”

“…Remarkably, this cluster contains the drug target candidate PA1624, whose inter-homodimer druggable interface has been previously suggested as a potential antimicrobial target. 81 The cluster is enriched in exposed proteins, and its centroid is the closest one to control virulence factors and antigens. Four cluster proteins satisfy the most stringent principles of strong vaccine B/T immunoantigen candidates with high human population coverage for the T helper response (HMPREF0010_00297, KPHS_35700, PA0222, and PA0360).…”