5WHU

Crystal structure of 3'SL bound ArtB

Summary for 5WHU

• Entry DOI: 10.2210/pdb5whu/pdb
• Related PRD ID: PRD_900025
• Descriptor: ArtB protein, N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose, N-acetyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose-(1-4)-alpha-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: bacterial toxin, glycan, toxin
• Biological source: Salmonella enterica subsp. enterica serovar Typhimurium str. DT104
• Total number of polymer chains: 10
• Total formula weight: 178410.03

Authors

Gao, X.,Galan, J.E. (deposition date: 2017-07-18, release date: 2017-10-25, Last modification date: 2024-10-30)

Primary citation

Gao, X.,Deng, L.,Stack, G.,Yu, H.,Chen, X.,Naito-Matsui, Y.,Varki, A.,Galan, J.E.
Evolution of host adaptation in the Salmonella typhoid toxin.
Nat Microbiol, 2:1592-1599, 2017

PubMed Abstract: The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host . Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi , the cause of typhoid fever in humans . Typhoid toxin has a unique AB architecture with two covalently linked enzymatic 'A' subunits, PltA and CdtB, associated with a homopentameric 'B' subunit made up of PltB, which has binding specificity for the N-acetylneuraminic acid (Neu5Ac) sialoglycans prominently present in humans . Here, we examine the functional and structural relationship between typhoid toxin and ArtAB, an evolutionarily related AB toxin encoded by the broad-host Salmonella Typhimurium . We find that ArtA and ArtB, homologues of PltA and PltB, can form a functional complex with the typhoid toxin CdtB subunit after substitution of a single amino acid in ArtA, while ArtB can form a functional complex with wild-type PltA and CdtB. We also found that, after addition of a single-terminal Cys residue, a CdtB homologue from cytolethal distending toxin can form a functional complex with ArtA and ArtB. In line with the broad host specificity of S. Typhimurium, we found that ArtB binds human glycans, terminated in N-acetylneuraminic acid, as well as glycans terminated in N-glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals . The atomic structure of ArtB bound to its receptor shows the presence of an additional glycan-binding site, which broadens its binding specificity. Despite equivalent toxicity in vitro, we found that the ArtB/PltA/CdtB chimaeric toxin exhibits reduced lethality in an animal model, indicating that the host specialization of typhoid toxin has optimized its targeting mechanisms to the human host. This is a remarkable example of a toxin evolving to broaden its enzymatic activities and adapt to a specific host.

PubMed: 28993610
DOI: 10.1038/s41564-017-0033-2

Experimental method

X-RAY DIFFRACTION (2.2 Å)