Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 298, Issue 5, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2022.101892
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Funding
- Academy of Finland [295296, 329252]
- Sigrid Juselius Foundation
- Instruct ERIC
- Finnish Society of Sciences and Letters
- University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine (TuDMM)
- Finnish Cultural Foundation
- Turku University Foundation
- Academy of Finland (AKA) [329252, 329252, 295296, 295296] Funding Source: Academy of Finland (AKA)
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Bordetella pertussis, the causative agent of whooping cough, secrets a toxin called pertussis toxin (PT) that can ADP-ribosylate host cells and interfere with G protein-coupled receptor signaling. This study provides crystal structures of the ADP-ribosyltransferase activity of PT, giving insights into the mechanism of ADP-ribosylation and potentially aiding in drug design.
Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum, where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the endoplasmic reticulum into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (G alpha i) of heterotrimeric G proteins, thus promoting dysregulation of G protein-coupled receptor signaling. However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. Here, we describe crystal structures of the S1 subunit in complex with nicotinamide adenine dinucleotide (NAD+), with NAD+ hydrolysis products ADP-ribose and nicotinamide, with NAD+ analog PJ34, and with a novel NAD+ analog formed upon S1 subunit crystallization with 3-amino benzamide and NAD+, which we name benzamide amino adenine dinucleotide. These crystal structures provide unprecedented insights into pre-and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. We propose that these data may aid in rational drug design approaches and further development of PT-specific small-molecule inhibitors.
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