7f3b

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==cocrystallization of Escherichia coli dihydrofolate reductase (DHFR) and its pyrrolo[3,2-f]quinazoline inhibitor.==
==cocrystallization of Escherichia coli dihydrofolate reductase (DHFR) and its pyrrolo[3,2-f]quinazoline inhibitor.==
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<StructureSection load='7f3b' size='340' side='right'caption='[[7f3b]]' scene=''>
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<StructureSection load='7f3b' size='340' side='right'caption='[[7f3b]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F3B FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7f3b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7F3B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7F3B FirstGlance]. <br>
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</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=7f3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f3b OCA], [https://pdbe.org/7f3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f3b RCSB], [https://www.ebi.ac.uk/pdbsum/7f3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f3b ProSAT]</span></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]] 2.81&#8491;</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=D4C:7-[(2-fluorophenyl)methyl]pyrrolo[3,2-f]quinazoline-1,3-diamine'>D4C</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=7f3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7f3b OCA], [https://pdbe.org/7f3b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7f3b RCSB], [https://www.ebi.ac.uk/pdbsum/7f3b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7f3b ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/DYR_ECOLI DYR_ECOLI] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The shortage of new antibiotics makes infections caused by gram-negative (G(-)) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G(-) strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 mug/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds.
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The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates.,Li Y, Ouyang Y, Wu H, Wang P, Huang Y, Li X, Chen H, Sun Y, Hu X, Wang X, Li G, Lu Y, Li C, Lu X, Pang J, Nie T, Sang X, Dong L, Dong W, Jiang J, Paterson IC, Yang X, Hong W, Wang H, You X Eur J Med Chem. 2022 Jan 15;228:113979. doi: 10.1016/j.ejmech.2021.113979. Epub, 2021 Nov 11. PMID:34802838<ref>PMID:34802838</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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<div class="pdbe-citations 7f3b" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Escherichia coli K-12]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Hong W]]
[[Category: Hong W]]

Current revision

cocrystallization of Escherichia coli dihydrofolate reductase (DHFR) and its pyrrolo[3,2-f]quinazoline inhibitor.

PDB ID 7f3b

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