7SKI

Pertussis toxin in complex with PJ34

Summary for 7SKI

• Entry DOI: 10.2210/pdb7ski/pdb
• Descriptor: Pertussis toxin subunit 1, N~2~,N~2~-DIMETHYL-N~1~-(6-OXO-5,6-DIHYDROPHENANTHRIDIN-2-YL)GLYCINAMIDE (3 entities in total)
• Functional Keywords: toxin, adp-ribosyltransferase, transferase, whooping cough, inhibitor, pertussis, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Bordetella pertussis
• Total number of polymer chains: 2
• Total formula weight: 41412.60

Authors

Littler, D.R.,Beddoe, T.,Pulliainen, A.,Rossjohn, J. (deposition date: 2021-10-20, release date: 2022-04-13, Last modification date: 2023-10-18)

Primary citation

Sakari, M.,Tran, M.T.,Rossjohn, J.,Pulliainen, A.T.,Beddoe, T.,Littler, D.R.
Crystal structures of pertussis toxin with NAD + and analogs provide structural insights into the mechanism of its cytosolic ADP-ribosylation activity.
J.Biol.Chem., 298:101892-101892, 2022

PubMed Abstract: 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 (Gαi) 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.

PubMed: 35378130
DOI: 10.1016/j.jbc.2022.101892

Experimental method

X-RAY DIFFRACTION (1.09912437248 Å)