View source for 5jic


==Staphylococcus aureus Type II pantothenate kinase in complex with a pantothenate analog==
<StructureSection load='5jic' size='340' side='right'caption='[[5jic]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5jic]] is a 1 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=5JIC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JIC 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]] 1.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N7E:N~3~-[(2R)-2-HYDROXY-3,3-DIMETHYL-4-(PHOSPHONOOXY)BUTANOYL]-N-(5-METHOXYPENTYL)-BETA-ALANINAMIDE'>N7E</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=5jic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jic OCA], [https://pdbe.org/5jic PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jic RCSB], [https://www.ebi.ac.uk/pdbsum/5jic PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jic ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/COAW_STAA8 COAW_STAA8] Catalyzes the phosphorylation of pantothenate (Pan), the first step in CoA biosynthesis.<ref>PMID:12760898</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) has been shown to at least partially be due to the inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. This mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. To dissect the molecular interactions responsible for PanAm inhibitory activity, we conducted a mini SAR study in tandem with the cocrystallization of SaPanKII with two classic PanAms (N5-Pan and N7-Pan), culminating in the synthesis and characterization of two new PanAms, N-Pip-PanAm and MeO-N5-PanAm. The cocrystal structures showed that all of the PanAms are phosphorylated by SaPanKII but remain bound at the active site; this occurs primarily through interactions with Tyr240' and Thr172'. Kinetic analysis showed a strong correlation between kcat (slow PanAm turnover) and IC50 (inhibition of pantothenate phosphorylation) values, suggesting that SaPanKII inhibition occurs via a delay in product release. In-depth analysis of the PanAm-bound structures showed that the capacity for accepting a hydrogen bond from the amide of Thr172' was a stronger determinant for PanAm potency than the capacity to pi-stack with Tyr240'. The two new PanAms, N-Pip-PanAm and MeO-N5-PanAm, effectively combine both hydrogen bonding and hydrophobic interactions, resulting in the most potent SaPanKII inhibition described to date. Taken together, our results are consistent with an inhibition mechanism wherein PanAms act as SaPanKII substrates that remain bound upon phosphorylation. The phospho-PanAm-SaPanKII interactions described herein may help future antistaphylococcal drug development.

Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product.,Hughes SJ, Barnard L, Mottaghi K, Tempel W, Antoshchenko T, Hong BS, Allali-Hassani A, Smil D, Vedadi M, Strauss E, Park HW ACS Infect Dis. 2016 Sep 9;2(9):627-641. Epub 2016 Aug 3. PMID:27759386<ref>PMID:27759386</ref>

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

==See Also==
*[[Pantothenate kinase 3D structures|Pantothenate kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus subsp. aureus MW2]]
[[Category: Antoshchenko T]]
[[Category: Barnard L]]
[[Category: Hughes SJ]]
[[Category: Mottaghi K]]
[[Category: Park H]]
[[Category: Strauss E]]