5ets: Difference between revisions

Latest revision as of 08:23, 12 July 2023

S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.95 angstrom resolution

Structural highlights

5ets is a 2 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.95Å
Ligands:	5RX, APC, MG, NA
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q2G0Q5_STAA8

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dennis ML, Pitcher NP, Lee MD, DeBono AJ, Wang ZC, Harjani JR, Rahmani R, Cleary B, Peat TS, Baell JB, Swarbrick JD. Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli. J Med Chem. 2016 Apr 26. PMID:27094768 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b00002

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OCA

[1] Dennis ML, Pitcher NP, Lee MD, DeBono AJ, Wang ZC, Harjani JR, Rahmani R, Cleary B, Peat TS, Baell JB, Swarbrick JD. Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli. J Med Chem. 2016 Apr 26. PMID:27094768 doi:https://dx.doi.org/10.1021/acs.jmedchem.6b00002

[1]

@@ Line 1: / Line 1: @@
 ==S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.95 angstrom resolution==
-<StructureSection load='5ets' size='340' side='right' caption='[[5ets]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='5ets' size='340' side='right'caption='[[5ets]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ets]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ETS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ETS FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ets]] 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=5ETS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ETS FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5RX:2-AZANYL-8-[(4-CHLOROPHENYL)METHYLSULFANYL]-1,9-DIHYDROPURIN-6-ONE'>5RX</scene>, <scene name='pdbligand=APC:DIPHOSPHOMETHYLPHOSPHONIC+ACID+ADENOSYL+ESTER'>APC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.95&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5etn|5etn]], [[5etk|5etk]], [[5etl|5etl]], [[5etm|5etm]], [[5eto|5eto]], [[5etp|5etp]], [[5etq|5etq]], [[5etr|5etr]], [[5ett|5ett]], [[5etv|5etv]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5RX:2-AZANYL-8-[(4-CHLOROPHENYL)METHYLSULFANYL]-1,9-DIHYDROPURIN-6-ONE'>5RX</scene>, <scene name='pdbligand=APC:DIPHOSPHOMETHYLPHOSPHONIC+ACID+ADENOSYL+ESTER'>APC</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/2-amino-4-hydroxy-6-hydroxymethyldihydropteridine_diphosphokinase 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.6.3 2.7.6.3] </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=5ets FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ets OCA], [https://pdbe.org/5ets PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ets RCSB], [https://www.ebi.ac.uk/pdbsum/5ets PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ets ProSAT]</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=5ets FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ets OCA], [http://pdbe.org/5ets PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ets RCSB], [http://www.ebi.ac.uk/pdbsum/5ets PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ets ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q2G0Q5_STAA8 Q2G0Q5_STAA8]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 5ets" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[HPPK 3D structures|HPPK 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]]
+[[Category: Large Structures]]
-[[Category: Dennis, M L]]
+[[Category: Staphylococcus aureus]]
-[[Category: Peat, T S]]
+[[Category: Dennis ML]]
-[[Category: Swarbrick, J D]]
+[[Category: Peat TS]]
-[[Category: Ampcpp]]
+[[Category: Swarbrick JD]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Pyrophosphokinase]]
-[[Category: Transferase-transferase inhibitor complex]]

5ets: Difference between revisions

Latest revision as of 08:23, 12 July 2023

S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.95 angstrom resolution

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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