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| | ==Crystal structure of E. coli HPPK in complex with bisubstrate analogue inhibitor J1B== | | ==Crystal structure of E. coli HPPK in complex with bisubstrate analogue inhibitor J1B== |
| - | <StructureSection load='3ude' size='340' side='right' caption='[[3ude]], [[Resolution|resolution]] 1.88Å' scene=''> | + | <StructureSection load='3ude' size='340' side='right'caption='[[3ude]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ude]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3UDE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3UDE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ude]] 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=3UDE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UDE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=J1B:5-S-[1-(2-{[(2-AMINO-7,7-DIMETHYL-4-OXO-3,4,7,8-TETRAHYDROPTERIDIN-6-YL)METHYL]AMINO}ETHYL)PIPERIDIN-4-YL]-5-THIOADENOSINE'>J1B</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]] 1.881Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ud5|3ud5]], [[3udv|3udv]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=J1B:5-S-[1-(2-{[(2-AMINO-7,7-DIMETHYL-4-OXO-3,4,7,8-TETRAHYDROPTERIDIN-6-YL)METHYL]AMINO}ETHYL)PIPERIDIN-4-YL]-5-THIOADENOSINE'>J1B</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">b0142, foIK, folK, JW0138 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</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=3ude FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ude OCA], [https://pdbe.org/3ude PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ude RCSB], [https://www.ebi.ac.uk/pdbsum/3ude PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ude ProSAT]</span></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>
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| - | <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=3ude FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ude OCA], [http://pdbe.org/3ude PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ude RCSB], [http://www.ebi.ac.uk/pdbsum/3ude PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ude ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/HPPK_ECOLI HPPK_ECOLI] |
| - | 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K(d) and IC(50) values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.
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| - | Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.,Shi G, Shaw G, Liang YH, Subburaman P, Li Y, Wu Y, Yan H, Ji X Bioorg Med Chem. 2012 Jan 1;20(1):47-57. Epub 2011 Nov 23. PMID:22169600<ref>PMID:22169600</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 3ude" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[6-hydroxymethyl-7%2C8-dihydropterin pyrophosphokinase|6-hydroxymethyl-7%2C8-dihydropterin pyrophosphokinase]] | + | *[[HPPK 3D structures|HPPK 3D structures]] |
| - | == References ==
| + | |
| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase]] | + | [[Category: Escherichia coli K-12]] |
| - | [[Category: Ecoli]] | + | [[Category: Large Structures]] |
| - | [[Category: Ji, X]] | + | [[Category: Ji X]] |
| - | [[Category: Shaw, G]] | + | [[Category: Shaw G]] |
| - | [[Category: Shi, G]] | + | [[Category: Shi G]] |
| - | [[Category: Alpha beta]]
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| - | [[Category: Atp binding]]
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| - | [[Category: Kinase]]
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| - | [[Category: Pyrophosphoryl transfer]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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