4m7u: Difference between revisions
New page: '''Unreleased structure''' The entry 4m7u is ON HOLD Authors: Bourne, C.R. Description: Dihydrofolate reductase from Enterococcus faecalis complexed with NADP(H) |
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The | ==Dihydrofolate reductase from Enterococcus faecalis complexed with NADP(H)== | ||
<StructureSection load='4m7u' size='340' side='right'caption='[[4m7u]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4m7u]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterococcus_faecalis_V583 Enterococcus faecalis V583]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M7U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4M7U 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]] 2.1014Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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=4m7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m7u OCA], [https://pdbe.org/4m7u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4m7u RCSB], [https://www.ebi.ac.uk/pdbsum/4m7u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4m7u ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q834R2_ENTFA Q834R2_ENTFA] 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] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We are addressing bacterial resistance to antibiotics by repurposing a well-established classic antimicrobial target, the dihydrofolate reductase (DHFR) enzyme. In this work, we have focused on Enterococcus faecalis, a nosocomial pathogen that frequently harbors antibiotic resistance determinants leading to complicated and difficult-to-treat infections. An inhibitor series with a hydrophobic dihydrophthalazine heterocycle was designed from the anti-folate trimethoprim. We have examined the potency of this inhibitor series based on inhibition of DHFR enzyme activity and bacterial growth, including in the presence of the exogenous product analogue folinic acid. The resulting preferences were rationalized using a cocrystal structure of the DHFR from this organism with a propyl-bearing series member (RAB-propyl). In a companion apo structure, we identify four buried waters that act as placeholders for a conserved hydrogen-bonding network to the substrate and indicate an important role in protein stability during catalytic cycling. In these structures, the nicotinamide of the nicotinamide adenine dinucleotide phosphate cofactor is visualized outside of its binding pocket, which is exacerbated by RAB-propyl binding. Finally, homology models of the TMP(R) sequences dfrK and dfrF were constructed. While the dfrK-encoded protein shows clear sequence changes that would be detrimental to inhibitor binding, the dfrF-encoded protein model suggests the protein would be relatively unstable. These data suggest a utility for anti-DHFR compounds for treating infections arising from E. faecalis. They also highlight a role for water in stabilizing the DHFR substrate pocket and for competitive substrate inhibitors that may gain advantages in potency by the perturbation of cofactor dynamics. | |||
The Structure and Competitive Substrate Inhibition of Dihydrofolate Reductase from Enterococcus faecalis Reveal Restrictions to Cofactor Docking.,Bourne CR, Wakeham N, Webb N, Nammalwar B, Bunce RA, Berlin KD, Barrow WW Biochemistry. 2014 Feb 25;53(7):1228-38. doi: 10.1021/bi401104t. Epub 2014 Feb, 11. PMID:24495113<ref>PMID:24495113</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4m7u" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Enterococcus faecalis V583]] | |||
[[Category: Large Structures]] | |||
[[Category: Bourne CR]] | |||
Latest revision as of 19:33, 20 September 2023
Dihydrofolate reductase from Enterococcus faecalis complexed with NADP(H)Dihydrofolate reductase from Enterococcus faecalis complexed with NADP(H)
Structural highlights
FunctionQ834R2_ENTFA 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] Publication Abstract from PubMedWe are addressing bacterial resistance to antibiotics by repurposing a well-established classic antimicrobial target, the dihydrofolate reductase (DHFR) enzyme. In this work, we have focused on Enterococcus faecalis, a nosocomial pathogen that frequently harbors antibiotic resistance determinants leading to complicated and difficult-to-treat infections. An inhibitor series with a hydrophobic dihydrophthalazine heterocycle was designed from the anti-folate trimethoprim. We have examined the potency of this inhibitor series based on inhibition of DHFR enzyme activity and bacterial growth, including in the presence of the exogenous product analogue folinic acid. The resulting preferences were rationalized using a cocrystal structure of the DHFR from this organism with a propyl-bearing series member (RAB-propyl). In a companion apo structure, we identify four buried waters that act as placeholders for a conserved hydrogen-bonding network to the substrate and indicate an important role in protein stability during catalytic cycling. In these structures, the nicotinamide of the nicotinamide adenine dinucleotide phosphate cofactor is visualized outside of its binding pocket, which is exacerbated by RAB-propyl binding. Finally, homology models of the TMP(R) sequences dfrK and dfrF were constructed. While the dfrK-encoded protein shows clear sequence changes that would be detrimental to inhibitor binding, the dfrF-encoded protein model suggests the protein would be relatively unstable. These data suggest a utility for anti-DHFR compounds for treating infections arising from E. faecalis. They also highlight a role for water in stabilizing the DHFR substrate pocket and for competitive substrate inhibitors that may gain advantages in potency by the perturbation of cofactor dynamics. The Structure and Competitive Substrate Inhibition of Dihydrofolate Reductase from Enterococcus faecalis Reveal Restrictions to Cofactor Docking.,Bourne CR, Wakeham N, Webb N, Nammalwar B, Bunce RA, Berlin KD, Barrow WW Biochemistry. 2014 Feb 25;53(7):1228-38. doi: 10.1021/bi401104t. Epub 2014 Feb, 11. PMID:24495113[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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