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| | <StructureSection load='4cyu' size='340' side='right'caption='[[4cyu]], [[Resolution|resolution]] 2.70Å' scene=''> | | <StructureSection load='4cyu' size='340' side='right'caption='[[4cyu]], [[Resolution|resolution]] 2.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cyu]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CYU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CYU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4cyu]] is a 4 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=4CYU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CYU 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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr> | + | </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=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</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=4cyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cyu OCA], [https://pdbe.org/4cyu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cyu RCSB], [https://www.ebi.ac.uk/pdbsum/4cyu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cyu 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=4cyu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cyu OCA], [http://pdbe.org/4cyu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cyu RCSB], [http://www.ebi.ac.uk/pdbsum/4cyu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cyu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]] | |
| | [[Category: Large Structures]] | | [[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: Folate]] | + | [[Category: Swarbrick JD]] |
| - | [[Category: S aureus]]
| + | |
| - | [[Category: Structure-based drug design]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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. 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. J Med Chem. 2014 Nov 26;57(22):9612-26. doi: 10.1021/jm501417f. Epub 2014 Nov 12. PMID:25357262 doi:http://dx.doi.org/10.1021/jm501417f
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