3frf: Difference between revisions

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<StructureSection load='3frf' size='340' side='right'caption='[[3frf]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
<StructureSection load='3frf' size='340' side='right'caption='[[3frf]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3frf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/"micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FRF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FRF FirstGlance]. <br>
<table><tr><td colspan='2'>[[3frf]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FRF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FRF FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=XCF:5-[[(2R)-2-CYCLOPROPYL-7,8-DIMETHOXY-2H-CHROMEN-5-YL]METHYL]PYRIMIDINE-2,4-DIAMINE'>XCF</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3fra|3fra]], [[3frb|3frb]], [[3frd|3frd]], [[3fre|3fre]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=XCF:5-[[(2R)-2-CYCLOPROPYL-7,8-DIMETHOXY-2H-CHROMEN-5-YL]METHYL]PYRIMIDINE-2,4-DIAMINE'>XCF</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">folA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1280 "Micrococcus aureus" (Rosenbach 1884) Zopf 1885])</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=3frf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3frf OCA], [https://pdbe.org/3frf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3frf RCSB], [https://www.ebi.ac.uk/pdbsum/3frf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3frf 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=3frf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3frf OCA], [https://pdbe.org/3frf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3frf RCSB], [https://www.ebi.ac.uk/pdbsum/3frf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3frf ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/DYR_STAAU DYR_STAAU]] 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_STAAU DYR_STAAU] 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=3frf 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=3frf ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
OBJECTIVES: Iclaprim is a novel 2,4-diaminopyrimidine that exhibits potent, rapid bactericidal activity against major Gram-positive pathogens, including methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus, and is currently in clinical development for the treatment of complicated skin and skin structure infections. An understanding of the known mechanism of resistance to trimethoprim led to the design of this new inhibitor, with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and clinically useful activity against S. aureus including isolates resistant to trimethoprim. The objective of this study was to characterize the mode of action of iclaprim and its inhibitory properties against DHFR. METHODS: The mode of action of iclaprim was assessed by enzymatic analysis, direct binding studies, macromolecular synthesis profiles, synergy and antagonism studies to define its role as an inhibitor of DHFR. The binding properties of iclaprim to DHFR were compared with those of trimethoprim by X-ray crystallography. RESULTS: The enzymatic properties, direct binding and X-ray crystallographic studies delineated the mode of interaction with DHFR and the reason for the increased affinity of iclaprim towards the enzyme. The effect of iclaprim on bacterial physiology suggests that iclaprim behaves as a classical antibacterial DHFR inhibitor, as previously documented for trimethoprim. CONCLUSIONS: Iclaprim binds and inhibits bacterial DHFR in a similar manner to trimethoprim. However, the increased hydrophobic interactions between iclaprim and DHFR account for increased affinity and, unlike trimethoprim, enable iclaprim to inhibit even the resistant enzyme with nanomolar affinity, thus overcoming the mechanism of trimethoprim resistance. The increased antibacterial activity and lower propensity for resistance make iclaprim a clinically promising and useful inhibitor.
Increased hydrophobic interactions of iclaprim with Staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity.,Oefner C, Bandera M, Haldimann A, Laue H, Schulz H, Mukhija S, Parisi S, Weiss L, Lociuro S, Dale GE J Antimicrob Chemother. 2009 Apr;63(4):687-98. Epub 2009 Feb 11. PMID:19211577<ref>PMID:19211577</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3frf" 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: Dihydrofolate reductase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Dale-Glenn, E]]
[[Category: Staphylococcus aureus]]
[[Category: Oefner, C]]
[[Category: Dale-Glenn E]]
[[Category: Dhfr]]
[[Category: Oefner C]]
[[Category: Nadp]]
[[Category: One-carbon metabolism]]
[[Category: Oxidoreductase]]

Latest revision as of 11:25, 20 March 2024

S. aureus DHFR complexed with NADPH and iclaprimS. aureus DHFR complexed with NADPH and iclaprim

Structural highlights

3frf is a 1 chain structure with sequence from Staphylococcus aureus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.2Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DYR_STAAU Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

3frf, resolution 2.20Å

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