View source for 5dhs


==Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a novel inhibitor==
<StructureSection load='5dhs' size='340' side='right'caption='[[5dhs]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5dhs]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Listeria_monocytogenes_EGD-e Listeria monocytogenes EGD-e]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DHS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DHS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5AG:5-AZIDO-5-DEOXY-8-[(2-{[2-(3-ETHYNYLPHENYL)ETHYL]AMINO}-2-OXOETHYL)SULFANYL]ADENOSINE'>5AG</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5dhs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dhs OCA], [https://pdbe.org/5dhs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dhs RCSB], [https://www.ebi.ac.uk/pdbsum/5dhs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dhs ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NADK1_LISMO NADK1_LISMO] 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]<ref>PMID:17686780</ref> <ref>PMID:22608967</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

8-Thioalkyl-adenosine derivatives inhibit Listeria monocytogenes NAD kinase through a novel binding mode.,Paoletti J, Assairi L, Gelin M, Huteau V, Nahori MA, Dussurget O, Labesse G, Pochet S Eur J Med Chem. 2016 Nov 29;124:1041-1056. doi: 10.1016/j.ejmech.2016.10.033., Epub 2016 Oct 18. PMID:27783975<ref>PMID:27783975</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5dhs" style="background-color:#fffaf0;"></div>

==See Also==
*[[NAD kinase|NAD kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Listeria monocytogenes EGD-e]]
[[Category: Assairi L]]
[[Category: Gelin M]]
[[Category: Huteau V]]
[[Category: Labesse G]]
[[Category: Paoletti J]]
[[Category: Pochet S]]