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Publication Abstract from PubMed

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 (ER), where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the ER into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Galphai) of heterotrimeric G proteins, thus promoting dysregulation of G-protein coupled receptor (GPCR) 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 (3AB) and NAD+, which we name benzamide amino adenine dinucleotide (BaAD). 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.

Crystal structures of pertussis toxin with NAD(+) and analogs provide structural insights into the mechanism of its cytosolic ADP-ribosylation activity.,Sakari M, Tran MT, Rossjohn J, Pulliainen AT, Beddoe T, Littler DR J Biol Chem. 2022 Apr 1:101892. doi: 10.1016/j.jbc.2022.101892. PMID:35378130^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.