Subversion of the host’s innate and adaptive immune systems is achieved through secretion of pertussis toxin (PT), a multifaceted protein complex that targets resident airway macrophages ( 6) and inhibits neutrophil recruitment at sites of infection to delay antibody-mediated clearance ( 7). Indeed, B. pertussis infection has become one of the most prevalent vaccine-preventable diseases.ī. pertussis expresses an array of virulence factors that promote bacterial adhesion and invasion but also prevent the onset of a protective immune responses ( 1). Moreover, developed nations have experienced rises in the number of pertussis cases reported this has been attributed to waning adult immunity ( 3), bacterial divergence from vaccine strains ( 4) and incomplete vaccine coverage ( 5). Vaccinated populations display marked morbidity reduction, but B. pertussis continues to circulate, providing a bacterial reservoir that can expand to cause endemic outbreaks. While pertussis-linked deaths continue to claim around 200,000 infants per year, the vast majority of such cases originate in areas of the world where immunization coverage is inadequate ( 2). Thankfully the historical burden of whooping cough has been dramatically curtailed by the widespread deployment of successful vaccination strategies now covering majority of the global population ( 1). B. pertussis infection is particularly dangerous for infants and young children where it may progress into whooping cough, a life-threatening respiratory disease ( 1). The highly contagious bacteria Bordetella pertussis infects millions of people each year. ![]() We propose that these data may aid in rational drug design approaches and further development of PT-specific small-molecule inhibitors. These crystal structures provide unprecedented insights into pre- and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. 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. ![]() However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. The released enzymatic S1 subunit is then translocated from the endoplasmic reticulum into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Gαi) of heterotrimeric G proteins, thus promoting dysregulation of G protein–coupled receptor signaling. ![]() The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum, where it subsequently dissociates. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease.
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