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[[ | ==Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a new di-adenosine inhibitor formed in situ== | ||
<StructureSection load='3v8p' size='340' side='right' caption='[[3v8p]], [[Resolution|resolution]] 2.29Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3v8p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Listeria_monocytogenes Listeria monocytogenes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V8P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V8P FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=ZNB:2-[6-AZANYL-9-[(2R,3R,4S,5R)-5-[[(AZANYLIDENE-$L^{4}-AZANYLIDENE)AMINO]METHYL]-3,4-BIS(OXIDANYL)OXOLAN-2-YL]PURIN-8-YL]SULFANYL-N-[[(2R,3S,4R,5R)-5-(6-AZANYL-8-BROMANYL-PURIN-9-YL)-3,4-BIS(OXIDANYL)OXOLAN-2-YL]METHYL]ETHANAMIDE'>ZNB</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2i2c|2i2c]], [[3v7v|3v7v]], [[3v7w|3v7w]], [[3v7y|3v7y]], [[3v80|3v80]], [[3v8m|3v8m]], [[3v8n|3v8n]], [[3v8q|3v8q]], [[3v8r|3v8r]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ppnK1, lmo0968 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1639 Listeria monocytogenes])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/NAD(+)_kinase NAD(+) kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.23 2.7.1.23] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v8p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v8p RCSB], [http://www.ebi.ac.uk/pdbsum/3v8p PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PPNK1_LISMO PPNK1_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.<ref>PMID:17686780</ref> <ref>PMID:22608967</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Making new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro. | |||
Screening and In Situ Synthesis Using Crystals of a NAD Kinase Lead to a Potent Antistaphylococcal Compound.,Gelin M, Poncet-Montange G, Assairi L, Morellato L, Huteau V, Dugue L, Dussurget O, Pochet S, Labesse G Structure. 2012 May 16. PMID:22608967<ref>PMID:22608967</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
< | |||
[[Category: Listeria monocytogenes]] | [[Category: Listeria monocytogenes]] | ||
[[Category: Assairi, L | [[Category: Assairi, L]] | ||
[[Category: Dugu, L | [[Category: Dugu, L]] | ||
[[Category: Dussurget, O | [[Category: Dussurget, O]] | ||
[[Category: Gelin, M | [[Category: Gelin, M]] | ||
[[Category: Huteau, V | [[Category: Huteau, V]] | ||
[[Category: Labesse, G | [[Category: Labesse, G]] | ||
[[Category: Morellato, L | [[Category: Morellato, L]] | ||
[[Category: Pochet, S | [[Category: Pochet, S]] | ||
[[Category: Poncet-Montange, G | [[Category: Poncet-Montange, G]] | ||
[[Category: Inorganic polyphosphate/atp-nad kinase 1]] | [[Category: Inorganic polyphosphate/atp-nad kinase 1]] | ||
[[Category: Ligand-screening by crystallography]] | [[Category: Ligand-screening by crystallography]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
[[Category: Two-domain kinase]] | [[Category: Two-domain kinase]] | ||
Revision as of 22:00, 24 December 2014
Crystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a new di-adenosine inhibitor formed in situCrystal structure of NAD kinase 1 from Listeria monocytogenes in complex with a new di-adenosine inhibitor formed in situ
Structural highlights
Function[PPNK1_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.[1] [2] Publication Abstract from PubMedMaking new ligands for a given protein by in situ ligation of building blocks (or fragments) is an attractive method. However, it suffers from inherent limitations, such as the limited number of available chemical reactions and the low information content of usual chemical library deconvolution. Here, we describe a focused screening of adenosine derivatives using X-ray crystallography. We discovered an unexpected and biocompatible chemical reactivity and have simultaneously identified the mode of binding of the resulting products. We observed that the NAD kinase from Listeria monocytogenes (LmNADK1) can promote amide formation between 5'-amino-5'-deoxyadenosine and carboxylic acid groups. This unexpected reactivity allowed us to bridge in situ two adenosine derivatives to fully occupy the active NAD site. This guided the design of a close analog showing micromolar inhibition of two human pathogenic NAD kinases and potent bactericidal activity against Staphylococcus aureus in vitro. Screening and In Situ Synthesis Using Crystals of a NAD Kinase Lead to a Potent Antistaphylococcal Compound.,Gelin M, Poncet-Montange G, Assairi L, Morellato L, Huteau V, Dugue L, Dussurget O, Pochet S, Labesse G Structure. 2012 May 16. PMID:22608967[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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