7ZZA

Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a linear di-adenosine derivative

Summary for 7ZZA

• Entry DOI: 10.2210/pdb7zza/pdb
• Related: 7ZZ7 7ZZ9
• Descriptor: NAD kinase 1, CITRIC ACID, 2-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-[3-[6-azanyl-9-[(2~{R},3~{R},4~{S},5~{R})-5-[(3-azanylpropylcarbamoylamino)methyl]-3,4-bis(oxidanyl)oxolan-2-yl]purin-8-yl]prop-2-ynyl]amino]ethanoic acid, ... (4 entities in total)
• Functional Keywords: tetrameric nad-kinase, transferase
• Biological source: Listeria monocytogenes EGD-e
• Total number of polymer chains: 1
• Total formula weight: 31964.10

Authors

Gelin, M.,Labesse, G. (deposition date: 2022-05-25, release date: 2023-01-11, Last modification date: 2024-01-31)

Primary citation

Clement, D.A.,Gelin, M.,Leseigneur, C.,Huteau, V.,Mondange, L.,Pons, J.L.,Dussurget, O.,Lionne, C.,Labesse, G.,Pochet, S.
Synthesis and structure-activity relationship studies of original cyclic diadenosine derivatives as nanomolar inhibitors of NAD kinase from pathogenic bacteria.
Eur.J.Med.Chem., 246:114941-114941, 2023

PubMed Abstract: Nicotinamide adenine dinucleotide kinases (NAD kinases) are essential and ubiquitous enzymes involved in the production of NADP(H) which is an essential cofactor in many metabolic pathways. Targeting NAD kinase (NADK), a rate limiting enzyme of NADP biosynthesis pathway, represents a new promising approach to treat bacterial infections. Previously, we have produced the first NADK inhibitor active against staphylococcal infection. From this linear di-adenosine derivative, namely NKI1, we designed macrocyclic analogues. Here, we describe the synthesis and evaluation of an original series of cyclic diadenosine derivatives as NADK inhibitors of two pathogenic bacteria, Listeria monocytogenes and Staphylococcus aureus. The nature and length of the link between the two adenosine units were examined leading to sub-micromolar inhibitors of NADK1 from L. monocytogenes, including its most potent in vitro inhibitor reported so far (with a 300-fold improvement compared to NKI1).

PubMed: 36455355
DOI: 10.1016/j.ejmech.2022.114941

Experimental method

X-RAY DIFFRACTION (2.05 Å)