7SKK

pertussis toxin in complex with ADPR and Nicotinamide

Summary for 7SKK

• Entry DOI: 10.2210/pdb7skk/pdb
• Related: 7SKI
• Descriptor: Pertussis toxin subunit 1, NICOTINAMIDE, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE, ... (5 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: 4
• Total formula weight: 86107.49

Authors

Littler, D.R.,Beddoe, T.,Pulliainen, A.,Rossjohn, J. (deposition date: 2021-10-21, 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 (1.65000771809 Å)