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4g8z

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==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==
==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==
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<StructureSection load='4g8z' size='340' side='right' caption='[[4g8z]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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<StructureSection load='4g8z' size='340' side='right'caption='[[4g8z]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4g8z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pneumocystis_jirovecii Pneumocystis jirovecii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G8Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G8Z FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4g8z]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pneumocystis_jirovecii Pneumocystis jirovecii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G8Z FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=TOP:TRIMETHOPRIM'>TOP</scene></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]] 1.75&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1dyr|1dyr]]</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=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=TOP:TRIMETHOPRIM'>TOP</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrofolate_reductase Dihydrofolate reductase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.3 1.5.1.3] </span></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=4g8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8z OCA], [https://pdbe.org/4g8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g8z RCSB], [https://www.ebi.ac.uk/pdbsum/4g8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8z ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4g8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g8z OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g8z RCSB], [http://www.ebi.ac.uk/pdbsum/4g8z PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/DYR_PNECA DYR_PNECA] 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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A major concern of immunocompromised patients, in particular those with AIDS, is susceptibility to infection caused by opportunistic pathogens such as Pneumocystis jirovecii, which is a leading cause of pneumonia in immunocompromised patients. We report the first kinetic and structural data for 2,4-diamino-6-[(2',5'-dichloro anilino)methyl]pyrido[2,3-d]pyrimidine (OAAG324), a potent inhibitor of dihydrofolate reductase (DHFR) from P. jirovecii (pjDHFR), and also for trimethoprim (TMP) and methotrexate (MTX) with pjDHFR, Pneumocystis carinii DHFR (pcDHFR), and human DHFR (hDHFR). OAAG324 shows a 9.0-fold selectivity for pjDHFR (Ki, 2.7 nM) compared to its selectivity for hDHFR (Ki, 24.4 nM), whereas there is only a 2.3-fold selectivity for pcDHFR (Ki, 6.3 nM). In order to understand the determinants of inhibitory potency, active-site mutations of pj-, pc-, and hDHFR were explored to make these enzymes more like each other. The most unexpected observations were that the variant pcDHFR forms with K37Q and K37Q/F69N mutations, which made the enzyme more like the human form, also made these enzymes more sensitive to the inhibitory activity of OAAG324, with Ki values of 0.26 and 0.71 nM, respectively. A similar gain in sensitivity was also observed for the hDHFR N64F variant, which showed a lower Ki value (0.58 nM) than native hDHFR, pcDHFR, or pjDHFR. Structural data are reported for complexes of OAAG324 with hDHFR and its Q35K and Q35S/N64F variants and for the complex of the K37S/F69N variant of pcDHFR with TMP. These results provide useful insight into the role of these residues in the optimization of highly selective inhibitors of DHFR against the opportunistic pathogen P. jirovecii.
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Kinetic and Structural Analysis for Potent Antifolate Inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and Human Dihydrofolate Reductases and Their Active-Site Variants.,Cody V, Pace J, Queener SF, Adair OO, Gangjee A Antimicrob Agents Chemother. 2013 Jun;57(6):2669-77. doi: 10.1128/AAC.00172-13., Epub 2013 Apr 1. PMID:23545530<ref>PMID:23545530</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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==See Also==
==See Also==
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*[[Dihydrofolate reductase|Dihydrofolate reductase]]
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*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Dihydrofolate reductase]]
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[[Category: Large Structures]]
[[Category: Pneumocystis jirovecii]]
[[Category: Pneumocystis jirovecii]]
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[[Category: Cody, V]]
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[[Category: Cody V]]
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[[Category: K37s and f69n mutation]]
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[[Category: Mutant pcdhfr inhibitor complex]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Tmp/nadph ligand]]
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Current revision

pcDHFR K37S/F69N double mutant TMP NADPH ternary complex

PDB ID 4g8z

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