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| | <StructureSection load='4m7x' size='340' side='right'caption='[[4m7x]], [[Resolution|resolution]] 1.42Å' scene=''> | | <StructureSection load='4m7x' size='340' side='right'caption='[[4m7x]], [[Resolution|resolution]] 1.42Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4m7x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Staaw Staaw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M7X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M7X FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4m7x]] 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=4M7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M7X FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=27Q:N-HEPTYL-N~3~-[(2R)-2-HYDROXY-3,3-DIMETHYL-4-(PHOSPHONOOXY)BUTANOYL]-BETA-ALANINAMIDE'>27Q</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=27Q:N-HEPTYL-N~3~-[(2R)-2-HYDROXY-3,3-DIMETHYL-4-(PHOSPHONOOXY)BUTANOYL]-BETA-ALANINAMIDE'>27Q</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4m7y|4m7y]]</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=4m7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m7x OCA], [https://pdbe.org/4m7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m7x RCSB], [https://www.ebi.ac.uk/pdbsum/4m7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m7x ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">coaW, MW2054 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=196620 STAAW])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantothenate_kinase Pantothenate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.33 2.7.1.33] </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=4m7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m7x OCA], [http://pdbe.org/4m7x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4m7x RCSB], [http://www.ebi.ac.uk/pdbsum/4m7x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4m7x ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/COAW_STAAW COAW_STAAW]] Catalyzes the phosphorylation of pantothenate (Pan), the first step in CoA biosynthesis (By similarity). | + | [https://www.uniprot.org/uniprot/COAW_STAAW COAW_STAAW] Catalyzes the phosphorylation of pantothenate (Pan), the first step in CoA biosynthesis (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Pantothenate kinase|Pantothenate kinase]] | + | *[[Pantothenate kinase 3D structures|Pantothenate kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pantothenate kinase]] | + | [[Category: Staphylococcus aureus subsp. aureus MW2]] |
| - | [[Category: Staaw]]
| + | [[Category: Hong B]] |
| - | [[Category: Hong, B]] | + | [[Category: Mottaghi K]] |
| - | [[Category: Mottaghi, K]] | + | [[Category: Park H]] |
| - | [[Category: Park, H]] | + | [[Category: Tempel W]] |
| - | [[Category: Tempel, W]] | + | |
| - | [[Category: Antibacterial]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
COAW_STAAW Catalyzes the phosphorylation of pantothenate (Pan), the first step in CoA biosynthesis (By similarity).
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hughes SJ, Barnard L, Mottaghi K, Tempel W, Antoshchenko T, Hong BS, Allali-Hassani A, Smil D, Vedadi M, Strauss E, Park HW. Discovery of Potent Pantothenamide Inhibitors of Staphylococcus aureus Pantothenate Kinase through a Minimal SAR Study: Inhibition Is Due to Trapping of the Product. ACS Infect Dis. 2016 Sep 9;2(9):627-641. Epub 2016 Aug 3. PMID:27759386 doi:http://dx.doi.org/10.1021/acsinfecdis.6b00090
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