3fl8: Difference between revisions
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==Crystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivative== | |||
<StructureSection load='3fl8' size='340' side='right'caption='[[3fl8]], [[Resolution|resolution]] 2.29Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3fl8]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FL8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FL8 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]] 2.2881Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=RAR:5-(3,4-DIMETHOXY-5-{(1E)-3-OXO-3-[(1S)-1-PROPYLPHTHALAZIN-2(1H)-YL]PROP-1-EN-1-YL}BENZYL)PYRIMIDINE-2,4-DIAMINE'>RAR</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=3fl8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fl8 OCA], [https://pdbe.org/3fl8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fl8 RCSB], [https://www.ebi.ac.uk/pdbsum/3fl8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fl8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fl/3fl8_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3fl8 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (< or =12.8 microg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P2(1)2(1)2(1), and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis. | |||
Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.,Bourne CR, Bunce RA, Bourne PC, Berlin KD, Barrow EW, Barrow WW Antimicrob Agents Chemother. 2009 Jul;53(7):3065-73. Epub 2009 Apr 13. PMID:19364848<ref>PMID:19364848</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3fl8" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bacillus anthracis]] | |||
[[Category: Large Structures]] | |||
[[Category: Barrow WW]] | |||
[[Category: Bourne CR]] | |||
Latest revision as of 09:47, 6 September 2023
Crystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivativeCrystal structure of B. anthracis dihydrofolate reductase (DHFR) with RAB1, a TMP-dihydrophthalazine derivative
Structural highlights
FunctionQ81R22_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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (< or =12.8 microg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P2(1)2(1)2(1), and X-ray diffraction data were collected to a 2.3-A resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis. Crystal structure of Bacillus anthracis dihydrofolate reductase with the dihydrophthalazine-based trimethoprim derivative RAB1 provides a structural explanation of potency and selectivity.,Bourne CR, Bunce RA, Bourne PC, Berlin KD, Barrow EW, Barrow WW Antimicrob Agents Chemother. 2009 Jul;53(7):3065-73. Epub 2009 Apr 13. PMID:19364848[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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