7qvs

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

spinqualitylabelsall models 7qvs, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qvs is a 2 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAP, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A071KS55_PSEAI Involved in the regulation of the intracellular balance of NAD and NADP, and is a key enzyme in the biosynthesis of NADP. Catalyzes specifically the phosphorylation on 2'-hydroxyl of the adenosine moiety of NAD to yield NADP.[HAMAP-Rule:MF_00361] Publication Abstract from PubMed 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 Ki of 4.6 mum. Moreover, this compound reduced P. aeruginosa infection in vivo in a zebrafish model. Structure-based design, synthesis and biological evaluation of a NAD(+) analogue targeting Pseudomonas aeruginosa NAD kinase.,Rahimova R, Nogaret P, Huteau V, Gelin M, Clement DA, Labesse G, Pochet S, Blanc-Potard AB, Lionne C FEBS J. 2022 Aug 29. doi: 10.1111/febs.16604. PMID:36036789 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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