7QVS

Pseudomonas aeruginosa nicotinamide adenine dinucleotide kinase (NADK) structure in complex with NADP

Summary for 7QVS

• Entry DOI: 10.2210/pdb7qvs/pdb
• Descriptor: NAD kinase, PHOSPHATE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: kinases, antibiotics, inhibitors, drug discovery, structural protein
• Biological source: Pseudomonas aeruginosa
• Total number of polymer chains: 2
• Total formula weight: 68181.63

Authors

Rahimova, R.,Gelin, M.,Labesse, G.,Lionne, C. (deposition date: 2022-01-23, release date: 2022-09-14, Last modification date: 2024-02-07)

Primary citation

Rahimova, R.,Nogaret, P.,Huteau, V.,Gelin, M.,Clement, D.A.,Labesse, G.,Pochet, S.,Blanc-Potard, A.B.,Lionne, C.
Structure-based design, synthesis and biological evaluation of a NAD + analogue targeting Pseudomonas aeruginosa NAD kinase.
Febs J., 290:482-501, 2023

PubMed Abstract: Multidrug resistance is a major public health problem that requires the urgent development of new antibiotics and therefore the identification of novel bacterial targets. The activity of nicotinamide adenine dinucleotide kinase, NADK, is essential in all bacteria tested so far, including many human pathogens that display antibiotic resistance leading to the failure of current treatments. Inhibiting NADK is therefore a promising and innovative antibacterial strategy since there is currently no drug on the market targeting this enzyme. Through a fragment-based drug design approach, we have recently developed a NAD -competitive inhibitor of NADKs, which displayed in vivo activity against Staphylococcus aureus. Here, we show that this compound, a di-adenosine derivative, is inactive against the NADK enzyme from the Gram-negative bacteria Pseudomonas aeruginosa (PaNADK). This lack of activity can be explained by the crystal structure of PaNADK, which was determined in complex with NADP in this study. Structural analysis led us to design and synthesize a benzamide adenine dinucleoside analogue, active against PaNADK. This novel compound efficiently inhibited PaNADK enzymatic activity in vitro with a K of 4.6 μm. Moreover, this compound reduced P. aeruginosa infection in vivo in a zebrafish model.

PubMed: 36036789
DOI: 10.1111/febs.16604

Experimental method

X-RAY DIFFRACTION (2.3 Å)