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==Inhibitors of 4-Phosphopanthetheine Adenylyltransferase==
<StructureSection load='4nat' size='340' side='right'caption='[[4nat]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4nat]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_MW2 Staphylococcus aureus subsp. aureus MW2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NAT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NAT FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2W5:(1R,2R)-N-(3,4-DICHLOROBENZYL)-2-(4,6-DIMETHOXYPYRIMIDIN-2-YL)CYCLOHEXANECARBOXAMIDE'>2W5</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</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=4nat FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nat OCA], [https://pdbe.org/4nat PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nat RCSB], [https://www.ebi.ac.uk/pdbsum/4nat PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nat ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/COAD_STAAW COAD_STAAW] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate (By similarity).
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== Publication Abstract from PubMed ==
Inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy.

Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.,de Jonge BL, Walkup GK, Lahiri SD, Huynh H, Neckermann G, Utley L, Nash TJ, Brock J, San Martin M, Kutschke A, Johnstone M, Laganas V, Hajec L, Gu RF, Ni H, Chen B, Hutchings K, Holt E, McKinney D, Gao N, Livchak S, Thresher J Antimicrob Agents Chemother. 2013 Dec;57(12):6005-15. doi: 10.1128/AAC.01661-13. , Epub 2013 Sep 16. PMID:24041904<ref>PMID:24041904</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4nat" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus subsp. aureus MW2]]
[[Category: Lahiri SD]]