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4elf

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==Structure-activity relationship guides enantiomeric preference among potent inhibitors of B. anthracis dihydrofolate reductase==
==Structure-activity relationship guides enantiomeric preference among potent inhibitors of B. anthracis dihydrofolate reductase==
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<StructureSection load='4elf' size='340' side='right' caption='[[4elf]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='4elf' size='340' side='right'caption='[[4elf]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4elf]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis_str._sterne Bacillus anthracis str. sterne]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ELF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ELF FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4elf]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis_str._Sterne Bacillus anthracis str. Sterne]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ELF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ELF FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35I:(2E)-3-{5-[(2,4-DIAMINOPYRIMIDIN-5-YL)METHYL]-2,3-DIMETHOXYPHENYL}-1-[(1S)-1-(3,3,3-TRIFLUOROPROPYL)PHTHALAZIN-2(1H)-YL]PROP-2-EN-1-ONE'>35I</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3fl8|3fl8]], [[3fl9|3fl9]], [[3ele|3ele]], [[3elb|3elb]], [[4elg|4elg]], [[4elh|4elh]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35I:(2E)-3-{5-[(2,4-DIAMINOPYRIMIDIN-5-YL)METHYL]-2,3-DIMETHOXYPHENYL}-1-[(1S)-1-(3,3,3-TRIFLUOROPROPYL)PHTHALAZIN-2(1H)-YL]PROP-2-EN-1-ONE'>35I</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BAS2083, BA_2237, dfrA, DHFR, GBAA_2237 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=260799 Bacillus anthracis str. Sterne])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4elf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4elf OCA], [https://pdbe.org/4elf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4elf RCSB], [https://www.ebi.ac.uk/pdbsum/4elf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4elf ProSAT]</span></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </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=4elf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4elf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4elf RCSB], [http://www.ebi.ac.uk/pdbsum/4elf PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/Q81R22_BACAN Q81R22_BACAN] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis (By similarity).[PIRNR:PIRNR000194]
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Background: Bacterial resistance to antibiotic therapies is increasing and new treatment options are badly needed. There is an overlap between these resistant bacteria and organisms classified as likely bioterror weapons. For example, Bacillus anthracis is innately resistant to the anti-folate trimethoprim due to sequence changes found in the dihydrofolate reductase enzyme. Development of new inhibitors provides an opportunity to enhance the current arsenal of anti-folate antibiotics while also expanding the coverage of the anti-folate class. Methods: We have characterized inhibitors of B. anthracis dihydrofolate reductase by measuring the K(i) and MIC values and calculating the energetics of binding. This series contains a core diaminopyrimidine ring, a central dimethoxybenzyl ring, and a dihydrophthalazine moiety. We have altered the chemical groups extended from a chiral center on the dihydropyridazine ring of the phthalazine moiety. The interactions for the most potent compounds were visualized by X-ray structure determination. Results: We find that the potency of individual enantiomers is divergent with clear preference for the S-enantiomer, while maintaining a high conservation of contacts within the binding site. The preference for enantiomers seems to be predicated largely by differential interactions with protein residues Leu29, Gln30 and Arg53. Conclusions: These studies have clarified the activity of modifications and of individual enantiomers, and highlighted the role of the less-active R-enantiomer in effectively diluting the more active S-enantiomer in racemic solutions. This directly contributes to the development of new antimicrobials, combating trimethoprim resistance, and treatment options for potential bioterrorism agents.
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Structure-activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase.,Bourne CR, Wakeham N, Nammalwar B, Tseitin V, Bourne PC, Barrow EW, Mylvaganam S, Ramnarayan K, Bunce RA, Berlin KD, Barrow WW Biochim Biophys Acta. 2013 Jan;1834(1):46-52. doi: 10.1016/j.bbapap.2012.09.001. , Epub 2012 Sep 20. PMID:22999981<ref>PMID:22999981</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Dihydrofolate reductase|Dihydrofolate reductase]]
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Bacillus anthracis str. sterne]]
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[[Category: Bacillus anthracis str. Sterne]]
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[[Category: Dihydrofolate reductase]]
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[[Category: Large Structures]]
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[[Category: Barrow, W W]]
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[[Category: Barrow WW]]
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[[Category: Bourne, C R]]
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[[Category: Bourne CR]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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Current revision

Structure-activity relationship guides enantiomeric preference among potent inhibitors of B. anthracis dihydrofolate reductase

PDB ID 4elf

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