5etq: Difference between revisions
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==S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.96 angstrom resolution== | |||
<StructureSection load='5etq' size='340' side='right'caption='[[5etq]], [[Resolution|resolution]] 1.96Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5etq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ETQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ETQ 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]] 1.96Å</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=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=YH2:4-{[(2-AMINO-6-OXO-6,9-DIHYDRO-1H-PURIN-8-YL)SULFANYL]METHYL}BENZONITRILE'>YH2</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=5etq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5etq OCA], [https://pdbe.org/5etq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5etq RCSB], [https://www.ebi.ac.uk/pdbsum/5etq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5etq ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q2G0Q5_STAA8 Q2G0Q5_STAA8] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a member of the folate biosynthesis pathway found in prokaryotes and lower eukaryotes that catalyzes the pyrophosphoryl transfer from the ATP cofactor to a 6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site inhibitors of HPPK and quantify binding against the E. coli and S. aureus enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues incorporating acetophenone-based substituents have comparable affinities for both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by X-ray crystallography. Differential chemical shift perturbation analysis confirmed this to be a common mode of binding for this series to SaHPPK. One compound (41) displayed binding affinities of 120 nM and 1.76 muM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK. | |||
Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli.,Dennis ML, Pitcher NP, Lee MD, DeBono AJ, Wang ZC, Harjani JR, Rahmani R, Cleary B, Peat TS, Baell JB, Swarbrick JD J Med Chem. 2016 Apr 26. PMID:27094768<ref>PMID:27094768</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Dennis | <div class="pdbe-citations 5etq" style="background-color:#fffaf0;"></div> | ||
[[Category: Peat | |||
[[Category: Swarbrick | ==See Also== | ||
*[[HPPK 3D structures|HPPK 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus]] | |||
[[Category: Dennis ML]] | |||
[[Category: Peat TS]] | |||
[[Category: Swarbrick JD]] | |||
Latest revision as of 11:23, 12 July 2023
S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.96 angstrom resolutionS. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.96 angstrom resolution
Structural highlights
FunctionPublication Abstract from PubMed6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a member of the folate biosynthesis pathway found in prokaryotes and lower eukaryotes that catalyzes the pyrophosphoryl transfer from the ATP cofactor to a 6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site inhibitors of HPPK and quantify binding against the E. coli and S. aureus enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues incorporating acetophenone-based substituents have comparable affinities for both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by X-ray crystallography. Differential chemical shift perturbation analysis confirmed this to be a common mode of binding for this series to SaHPPK. One compound (41) displayed binding affinities of 120 nM and 1.76 muM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK. Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli.,Dennis ML, Pitcher NP, Lee MD, DeBono AJ, Wang ZC, Harjani JR, Rahmani R, Cleary B, Peat TS, Baell JB, Swarbrick JD J Med Chem. 2016 Apr 26. PMID:27094768[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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