A1 Refereed original research article in a scientific journal
Crystal structures of pertussis toxin with NAD(+) and analogs provide structural insights into the mechanism of its cytosolic ADP-ribosylation activity
Authors: Sakari Moona, Tran Mai T, Rossjohn Jamie, Pulliainen Arto T, Beddoe Travis, Littler Dene R
Publisher: ELSEVIER
Publication year: 2022
Journal: Journal of Biological Chemistry
Journal name in source: JOURNAL OF BIOLOGICAL CHEMISTRY
Journal acronym: J BIOL CHEM
Article number: 101892
Volume: 298
Issue: 5
Number of pages: 13
eISSN: 1067-8816
DOI: https://doi.org/10.1016/j.jbc.2022.101892
Web address : https://www.sciencedirect.com/science/article/pii/S0021925822003325
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175740287
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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