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| | ==E. coli dihydropteroate synthase complexed with an 8-mercaptoguanine derivative: 2-((2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-phenylacetamide== | | ==E. coli dihydropteroate synthase complexed with an 8-mercaptoguanine derivative: 2-((2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)-N-phenylacetamide== |
| - | <StructureSection load='5v79' size='340' side='right' caption='[[5v79]], [[Resolution|resolution]] 2.25Å' scene=''> | + | <StructureSection load='5v79' size='340' side='right'caption='[[5v79]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5v79]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecol6 Ecol6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V79 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V79 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5v79]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_CFT073 Escherichia coli CFT073]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V79 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V79 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8Y4:2-[(2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)sulfanyl]-N-phenylacetamide'>8Y4</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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]] 2.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5u0v|5u0v]], [[5u0y|5u0y]], [[5u0x|5u0x]], [[5u0w|5u0w]], [[5u10|5u10]], [[5u13|5u13]], [[5u12|5u12]], [[5u11|5u11]], [[5u0z|5u0z]], [[5u14|5u14]], [[5v7a|5v7a]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8Y4:2-[(2-amino-9-methyl-6-oxo-6,9-dihydro-1H-purin-8-yl)sulfanyl]-N-phenylacetamide'>8Y4</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folP, c3933 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=199310 ECOL6])</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=5v79 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v79 OCA], [https://pdbe.org/5v79 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v79 RCSB], [https://www.ebi.ac.uk/pdbsum/5v79 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v79 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/Dihydropteroate_synthase Dihydropteroate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.15 2.5.1.15] </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=5v79 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v79 OCA], [http://pdbe.org/5v79 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v79 RCSB], [http://www.ebi.ac.uk/pdbsum/5v79 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v79 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DHPS_ECOL6 DHPS_ECOL6]] Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.[UniProtKB:P0AC13] | + | [https://www.uniprot.org/uniprot/DHPS_ECOLI DHPS_ECOLI] DHPS catalyzes the formation of the immediate precursor of folic acid. It is implicated in resistance to sulfonamide.<ref>PMID:368012</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5v79" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5v79" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dihydropteroate synthase 3D structures|Dihydropteroate synthase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydropteroate synthase]] | + | [[Category: Escherichia coli CFT073]] |
| - | [[Category: Ecol6]] | + | [[Category: Large Structures]] |
| - | [[Category: Dennis, M L]] | + | [[Category: Dennis ML]] |
| - | [[Category: Peat, T S]] | + | [[Category: Peat TS]] |
| - | [[Category: Swarbrick, J D]] | + | [[Category: Swarbrick JD]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Dhp]]
| + | |
| - | [[Category: Pterin site]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
DHPS_ECOLI DHPS catalyzes the formation of the immediate precursor of folic acid. It is implicated in resistance to sulfonamide.[1]
Publication Abstract from PubMed
Dihydropteroate synthase (DHPS) is an enzyme of the folate biosynthesis pathway which catalyzes the formation of 7,8-dihydropteroate (DHPt) from 6-hydroxymethyl-7,8-dihydropterin pyrophosphate (DHPPP) and para-aminobenzoic acid (pABA). DHPS is the long-standing target of the sulfonamide class of antibiotics that compete with pABA. In the wake of sulfa drug resistance, targeting the structurally rigid (and more conserved) pterin site has been proposed as an alternate strategy to inhibit DHPS in wild-type and sulfa drug resistant strains. Following work developing pterin-site inhibitors of the adjacent enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), we now present derivatives of 8-mercaptoguanine, a fragment that binds weakly within both enzymes, and quantify sub-muM binding using Surface Plasmon Resonance (SPR) to Escherichia coli DHPS (EcDHPS). Eleven ligand-bound EcDHPS crystal structures delineate the structure-activity relationship observed providing a structural framework for the rational development of novel, substrate envelope-compliant DHPS inhibitors.
8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase.,Swarbrick J, Dennis M, Lee M, Harjani J, Ahmed M, Debono A, Pitcher N, Wang ZC, Chhabra S, Barlow N, Rahmani R, Cleary B, Dolezal O, Hattarki M, Aurelio L, Shonberg J, Graham B, Peat T, Baell J Chemistry. 2017 Nov 24. doi: 10.1002/chem.201704730. PMID:29171692[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Swedberg G, Castensson S, Skold O. Characterization of mutationally altered dihydropteroate synthase and its ability to form a sulfonamide-containing dihydrofolate analog. J Bacteriol. 1979 Jan;137(1):129-36. PMID:368012
- ↑ Swarbrick J, Dennis M, Lee M, Harjani J, Ahmed M, Debono A, Pitcher N, Wang ZC, Chhabra S, Barlow N, Rahmani R, Cleary B, Dolezal O, Hattarki M, Aurelio L, Shonberg J, Graham B, Peat T, Baell J. 8-Mercaptoguanine derivatives as inhibitors of dihydropteroate synthase. Chemistry. 2017 Nov 24. doi: 10.1002/chem.201704730. PMID:29171692 doi:http://dx.doi.org/10.1002/chem.201704730
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