5DHQ

Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a novel inhibitor

Summary for 5DHQ

• Entry DOI: 10.2210/pdb5dhq/pdb
• Related: 5DHP 5DHR 5DHS 5DHT 5DHU
• Descriptor: NAD kinase 1, CITRIC ACID, 8-[(2-{[2-(3-bromophenyl)ethyl]amino}-2-oxoethyl)sulfanyl]adenosine, ... (5 entities in total)
• Functional Keywords: tetrameric nad kinase, transferase
• Biological source: Listeria monocytogenes serovar 1/2a (strain ATCC BAA-679 / EGD-e)
• Cellular location: Cytoplasm : Q8Y8D7
• Total number of polymer chains: 4
• Total formula weight: 126815.07

Authors

Gelin, M.,Paoletti, J.,Assairi, L.,Huteau, V.,Pochet, S.,Labesse, G. (deposition date: 2015-08-31, release date: 2016-09-14, Last modification date: 2024-01-10)

Primary citation

Paoletti, J.,Assairi, L.,Gelin, M.,Huteau, V.,Nahori, M.A.,Dussurget, O.,Labesse, G.,Pochet, S.
8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode.
Eur.J.Med.Chem., 124:1041-1056, 2016

PubMed Abstract: Increased resistance of pathogens to existing antibiotics necessitates the search for novel targets to develop potent antimicrobials. Biosynthetic pathways of several cofactors important for bacterial growth, such as nicotinamide adenine dinucleotide phosphate (NADP), have been proposed as a promising source of antibiotic targets. Nicotinamide adenine dinucleotide kinases (NADK; EC 2.7.1.23) are attractive for inhibitor development, since they catalyze the phosphorylation of NAD to NADP, which is an essential step of NADP metabolism. We previously synthesized diadenosine derivatives that inhibited NADK from two human pathogens, Listeria monocytogenes and Staphylococcus aureus, in the micromolar range. They behave as NAD mimics with the 5',5'-diphosphate group substituted by a 8,5' thioglycolic bridge. In an attempt to improve inhibitory potency, we designed new NAD mimics based on a single adenosine moiety harboring a larger derivatization attached to the C8 position and a small group at the 5' position. Here we report the synthesis of a series of 8-thioalkyl-adenosine derivatives containing various aryl and heteroaryl moieties and their evaluation as inhibitors of L. monocytogenes NADK1, S. aureus NADK and their human counterpart. Novel, sub-micromolar inhibitors of LmNADK1 were identified. Surprisingly, most LmNADK1 inhibitors demonstrated a high selectivity index against the close staphylococcal ortholog and the human NADK. Structural characterization of enzyme-inhibitor complexes revealed the original binding mode of these novel NAD mimics.

PubMed: 27783975
DOI: 10.1016/j.ejmech.2016.10.033

Experimental method

X-RAY DIFFRACTION (2.29 Å)