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==Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(3-chlorophenethyl)-1H-benzo[d]imidazol-4-ol==
==Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(3-chlorophenethyl)-1H-benzo[d]imidazol-4-ol==
<StructureSection load='6ccq' size='340' side='right' caption='[[6ccq]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
<StructureSection load='6ccq' size='340' side='right'caption='[[6ccq]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6ccq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CCQ FirstGlance]. <br>
<table><tr><td colspan='2'>[[6ccq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CCQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CCQ FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EX7:2-[2-(3-chlorophenyl)ethyl]-1H-benzimidazol-7-ol'>EX7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.92&#8491;</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EX7:2-[2-(3-chlorophenyl)ethyl]-1H-benzimidazol-7-ol'>EX7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6ccq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccq OCA], [http://pdbe.org/6ccq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ccq RCSB], [http://www.ebi.ac.uk/pdbsum/6ccq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccq ProSAT]</span></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=6ccq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ccq OCA], [https://pdbe.org/6ccq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ccq RCSB], [https://www.ebi.ac.uk/pdbsum/6ccq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ccq ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/COAD_ECOLI COAD_ECOLI]] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.  
[https://www.uniprot.org/uniprot/COAD_ECOLI COAD_ECOLI] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria is a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli DeltatolC mutant strain.
 
Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.,Moreau RJ, Skepper CK, Appleton BA, Blechschmidt A, Balibar CJ, Benton BM, Drumm JE, Feng BY, Geng M, Li C, Lindvall MK, Lingel A, Lu Y, Mamo M, Mergo W, Polyakov V, Smith TM, Takeoka K, Uehara K, Wang L, Wei JR, Weiss AH, Xie L, Xu W, Zhang Q, de Vicente J J Med Chem. 2018 Mar 2. doi: 10.1021/acs.jmedchem.7b01691. PMID:29498517<ref>PMID:29498517</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ccq" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Pantetheine-phosphate adenylyltransferase]]
[[Category: Escherichia coli K-12]]
[[Category: Appleton, B A]]
[[Category: Large Structures]]
[[Category: Mamo, M]]
[[Category: Appleton BA]]
[[Category: Ppat coad fbdd phosphopantetheine adenylyltransferase gram-negative antibacterial antibiotic]]
[[Category: Mamo M]]
[[Category: Transferase-antibiotic complex]]

Latest revision as of 17:27, 13 March 2024

Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(3-chlorophenethyl)-1H-benzo[d]imidazol-4-olCrystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with 2-(3-chlorophenethyl)-1H-benzo[d]imidazol-4-ol

Structural highlights

6ccq is a 2 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.92Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

COAD_ECOLI Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.

6ccq, resolution 1.92Å

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