4cwb: Difference between revisions
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==Staphylococcus aureus 7,8-Dihydro-6-hydroxymethylpterin- pyrophosphokinase in complex with AMPCPP and an inhibitor== | |||
<StructureSection load='4cwb' size='340' side='right'caption='[[4cwb]], [[Resolution|resolution]] 1.56Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4cwb]] is a 1 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=4CWB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CWB 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]] 1.56Å</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=X6L:2-AMINO-8-[2-OXO-2-(4-PHENYLPHENYL)ETHYL]SULFANYL-1,9-DIHYDROPURIN-6-ONE'>X6L</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=4cwb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cwb OCA], [https://pdbe.org/4cwb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cwb RCSB], [https://www.ebi.ac.uk/pdbsum/4cwb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cwb ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 A upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors. | |||
Structure-based design and development of functionalized Mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus.,Dennis ML, Chhabra S, Wang ZC, Debono A, Dolezal O, Newman J, Pitcher NP, Rahmani R, Cleary B, Barlow N, Hattarki M, Graham B, Peat TS, Baell JB, Swarbrick JD J Med Chem. 2014 Nov 26;57(22):9612-26. doi: 10.1021/jm501417f. Epub 2014 Nov 12. PMID:25357262<ref>PMID:25357262</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Dennis | <div class="pdbe-citations 4cwb" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==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 15:17, 20 December 2023
Staphylococcus aureus 7,8-Dihydro-6-hydroxymethylpterin- pyrophosphokinase in complex with AMPCPP and an inhibitorStaphylococcus aureus 7,8-Dihydro-6-hydroxymethylpterin- pyrophosphokinase in complex with AMPCPP and an inhibitor
Structural highlights
Publication Abstract from PubMed6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 A upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors. Structure-based design and development of functionalized Mercaptoguanine derivatives as inhibitors of the folate biosynthesis pathway enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase from Staphylococcus aureus.,Dennis ML, Chhabra S, Wang ZC, Debono A, Dolezal O, Newman J, Pitcher NP, Rahmani R, Cleary B, Barlow N, Hattarki M, Graham B, Peat TS, Baell JB, Swarbrick JD J Med Chem. 2014 Nov 26;57(22):9612-26. doi: 10.1021/jm501417f. Epub 2014 Nov 12. PMID:25357262[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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