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==The Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase== | ==The Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase== | ||
<StructureSection load='4m5g' size='340' side='right' caption='[[4m5g]], [[Resolution|resolution]] 1.31Å' scene=''> | <StructureSection load='4m5g' size='340' side='right'caption='[[4m5g]], [[Resolution|resolution]] 1.31Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4m5g]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4m5g]] is a 1 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=4M5G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M5G FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=APC:DIPHOSPHOMETHYLPHOSPHONIC+ACID+ADENOSYL+ESTER'>APC</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=YH1:2-AMINO-8-[(2-OXO-2-PHENYLETHYL)SULFANYL]-1,9-DIHYDRO-6H-PURIN-6-ONE'>YH1</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.31Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=APC:DIPHOSPHOMETHYLPHOSPHONIC+ACID+ADENOSYL+ESTER'>APC</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=YH1:2-AMINO-8-[(2-OXO-2-PHENYLETHYL)SULFANYL]-1,9-DIHYDRO-6H-PURIN-6-ONE'>YH1</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=4m5g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m5g OCA], [https://pdbe.org/4m5g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m5g RCSB], [https://www.ebi.ac.uk/pdbsum/4m5g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m5g ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/HPPK_ECOLI HPPK_ECOLI] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 17: | Line 18: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4m5g" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[ | *[[HPPK 3D structures|HPPK 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Escherichia coli K-12]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Hoagland | [[Category: Hoagland D]] | ||
[[Category: Kumar | [[Category: Kumar G]] | ||
[[Category: Lee | [[Category: Lee RE]] | ||
[[Category: Rock | [[Category: Rock CO]] | ||
[[Category: Waddell | [[Category: Waddell B]] | ||
[[Category: White | [[Category: White SW]] | ||
[[Category: Yun | [[Category: Yun M]] | ||
Latest revision as of 19:32, 20 September 2023
The Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinaseThe Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase
Structural highlights
FunctionPublication Abstract from PubMed6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the microbial folate biosynthetic pathway. This pathway has proven to be an excellent target for antimicrobial development, but widespread resistance to common therapeutics including the sulfa drugs has stimulated interest in HPPK as an alternative target in the pathway. A screen of a pterin-biased compound set identified several HPPK inhibitors that contain an aryl substituted 8-thioguanine scaffold, and structural analyses showed that these compounds engage the HPPK pterin-binding pocket and an induced cryptic pocket. A preliminary structure activity relationship profile was developed from biophysical and biochemical characterizations of derivative molecules. Also, a similarity search identified additional scaffolds that bind more tightly within the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid elaboration into novel lead antimicrobial agents. The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.,Yun MK, Hoagland D, Kumar G, Waddell MB, Rock CO, Lee RE, White SW Bioorg Med Chem. 2014 Apr 1;22(7):2157-65. doi: 10.1016/j.bmc.2014.02.022. Epub, 2014 Feb 25. PMID:24613625[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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