3i8a

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[[Image:3i8a.png|left|200px]]
 
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==Staphylococcus aureus H30N, F98Y Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)==
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The line below this paragraph, containing "STRUCTURE_3i8a", creates the "Structure Box" on the page.
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<StructureSection load='3i8a' size='340' side='right'caption='[[3i8a]], [[Resolution|resolution]] 2.41&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3i8a]] 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=3I8A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3I8A FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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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]] 2.41&#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=N22:5-[3-(2,5-DIMETHOXYPHENYL)PROP-1-YN-1-YL]-6-ETHYLPYRIMIDINE-2,4-DIAMINE'>N22</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
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{{STRUCTURE_3i8a| PDB=3i8a | SCENE= }}
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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=3i8a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3i8a OCA], [https://pdbe.org/3i8a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3i8a RCSB], [https://www.ebi.ac.uk/pdbsum/3i8a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3i8a ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i8/3i8a_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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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=3i8a ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Resistance to therapeutics such as trimethoprim-sulfamethoxazole has become an increasing problem in strains of methicillin-resistant Staphylococcus aureus (MRSA). Clinically isolated trimethoprim-resistant strains reveal a double mutation, H30N/F98Y, in dihydrofolate reductase (DHFR). In order to develop novel and effective therapeutics against these resistant strains, we evaluated a series of propargyl-linked antifolate lead compounds for inhibition of the mutant enzyme. For the propargyl-linked antifolates, the F98Y mutation generates minimal (between 1.2- and 6-fold) losses of affinity and the H30N mutation generates greater losses (between 2.4- and 48-fold). Conversely, trimethoprim affinity is largely diminished by the F98Y mutation (36-fold) and is not affected by the H30N mutation. In order to elucidate a mechanism of resistance, we determined a crystal structure of a complex of this double mutant with a lead propargyl-linked antifolate. This structure suggests a resistance mechanism consistent both for the propargyl-linked class of antifolates and for trimethoprim that is based on the loss of a conserved water-mediated hydrogen bond.
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===Staphylococcus aureus H30N, F98Y Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)===
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Towards the understanding of resistance mechanisms in clinically isolated trimethoprim-resistant, methicillin-resistant Staphylococcus aureus dihydrofolate reductase.,Frey KM, Lombardo MN, Wright DL, Anderson AC J Struct Biol. 2010 Apr;170(1):93-7. Epub 2009 Dec 21. PMID:20026215<ref>PMID:20026215</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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The line below this paragraph, {{ABSTRACT_PUBMED_20026215}}, adds the Publication Abstract to the page
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<div class="pdbe-citations 3i8a" style="background-color:#fffaf0;"></div>
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(as it appears on PubMed at http://www.pubmed.gov), where 20026215 is the PubMed ID number.
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{{ABSTRACT_PUBMED_20026215}}
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==About this Structure==
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[[3i8a]] is a 1 chain structure of [[Dihydrofolate reductase]] with sequence from [http://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3I8A OCA].
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==See Also==
==See Also==
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*[[Dihydrofolate reductase]]
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:20026215</ref><references group="xtra"/>
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__TOC__
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[[Category: Dihydrofolate reductase]]
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</StructureSection>
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[[Category: Large Structures]]
[[Category: Staphylococcus aureus]]
[[Category: Staphylococcus aureus]]
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[[Category: Anderson, A C.]]
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[[Category: Anderson AC]]
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[[Category: Frey, K M.]]
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[[Category: Frey KM]]
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[[Category: Lombardo, M N.]]
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[[Category: Lombardo MN]]
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[[Category: Nadp]]
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[[Category: One-carbon metabolism]]
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[[Category: Oxidoreductase]]
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Current revision

Staphylococcus aureus H30N, F98Y Dihydrofolate Reductase complexed with NADPH and 2,4-diamino-5-(3-(2,5-dimethoxyphenyl)prop-1-ynyl)-6-ethylpyrimidine (UCP120B)

PDB ID 3i8a

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