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==DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEX WITH BRODIMOPRIM-4,6-DICARBOXYLATE==
==DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEX WITH BRODIMOPRIM-4,6-DICARBOXYLATE==
<StructureSection load='1dis' size='340' side='right'caption='[[1dis]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''>
<StructureSection load='1dis' size='340' side='right'caption='[[1dis]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1dis]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_a"_von_freudenreich_1890 "bacillus a" von freudenreich 1890]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DIS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DIS FirstGlance]. <br>
<table><tr><td colspan='2'>[[1dis]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lacticaseibacillus_casei Lacticaseibacillus casei]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DIS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DIS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BDM:BRODIMOPRIM-4,6-DICARBOXYLATE'>BDM</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1diu|1diu]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BDM:BRODIMOPRIM-4,6-DICARBOXYLATE'>BDM</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">POTENTIAL ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1582 "Bacillus a" von Freudenreich 1890])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></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=1dis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dis OCA], [https://pdbe.org/1dis PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dis RCSB], [https://www.ebi.ac.uk/pdbsum/1dis PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dis ProSAT]</span></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=1dis FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dis OCA], [https://pdbe.org/1dis PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dis RCSB], [https://www.ebi.ac.uk/pdbsum/1dis PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dis ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/DYR_LACCA DYR_LACCA]] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.  
[https://www.uniprot.org/uniprot/DYR_LACCA DYR_LACCA] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</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=1dis ConSurf].
</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=1dis ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Two-dimensional (2D) double-quantum-filtered correlation spectroscopy (DQF-COSY), total correlation spectroscopy (TOCSY), nuclear Overhauser effect spectroscopy (NOESY), and rotating-frame NOESY (ROESY) spectra were used to assign essentially all the protons in a 1:1 complex of Lactobacillus casei dihydrofolate reductase formed with an analogue of the antibacterial drug brodimoprim [2,4-diamino-5-(3',5'-dimethoxy-4'-bromobenzyl)pyrimidine]. The analogue has a 4,6-dicarboxylic acid side chain substituted on the 3'-O position designed to interact with the Arg 57 and His 28 residues in L. casei dihydrofolate reductase; it binds a factor of 10(3) more tightly to the enzyme than does the parent compound. Thirty-eight intermolecular and 11 intramolecular NOEs were measured involving the bound brodimoprim-4,6-dicarboxylic acid analogue. These provided the distance constraints used in conjunction with an energy minimization and simulated annealing protocol (using Discover from Biosym Ltd.) to dock the brodimoprim analogue into dihydrofolate reductase. In calculations where side chains and backbone fragments for binding-site residues were allowed flexibility, 90% of the 40 calculated structures had reasonable covalent geometry and none of them had NOE distance violations of greater than 0.36 A. The conformations of the aromatic rings in the bound ligand were well-defined in all the structures, with torsion angles tau 1 = -153 degrees +/- 4 degrees (C4-C5-C7-C1') and tau 2 = 53 degrees +/- 4 degrees (C5-C7-C1'-C2'): the aromatic rings of the ligand occupied essentially the same space in all the calculated structures (root mean square deviation value 1.83 A). Inclusion of the electrostatic interactions into the energy minimizations indicated that structures in which the 4,6-dicarboxylate group of the ligand interacts with the side chains of Arg 57 and His 28 are of low energy. Significant differences in side-chain and backbone conformations were detected between binding-site residues in the enzyme complexes with the brodimorpim analogue and methotrexate.
Solution structure of a brodimoprim analogue in its complex with Lactobacillus casei dihydrofolate reductase.,Morgan WD, Birdsall B, Polshakov VI, Sali D, Kompis I, Feeney J Biochemistry. 1995 Sep 19;34(37):11690-702. PMID:7547901<ref>PMID:7547901</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1dis" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bacillus a von freudenreich 1890]]
[[Category: Lacticaseibacillus casei]]
[[Category: Dihydrofolate reductase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Birdsall, B]]
[[Category: Birdsall B]]
[[Category: Feeney, J]]
[[Category: Feeney J]]
[[Category: Kompis, I]]
[[Category: Kompis I]]
[[Category: Morgan, W D]]
[[Category: Morgan WD]]
[[Category: Polshakov, V I]]
[[Category: Polshakov VI]]
[[Category: Sali, D]]
[[Category: Sali D]]
[[Category: Inhibitor-enzyme complex]]
[[Category: Oxido-reductase]]
[[Category: Oxidoreductase]]

Revision as of 09:50, 20 March 2024

DIHYDROFOLATE REDUCTASE (E.C.1.5.1.3) COMPLEX WITH BRODIMOPRIM-4,6-DICARBOXYLATE

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