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| | <StructureSection load='4g8z' size='340' side='right'caption='[[4g8z]], [[Resolution|resolution]] 1.75Å' scene=''> | | <StructureSection load='4g8z' size='340' side='right'caption='[[4g8z]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4g8z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_pneumocystis_pneumonia_agent Human pneumocystis pneumonia agent]. 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> | + | <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> |
| - | </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> | + | </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=TOP:TRIMETHOPRIM'>TOP</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1dyr|1dyr]]</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=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> |
| - | <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>
| + | |
| - | <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://pdbe.org/4g8z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4g8z RCSB], [http://www.ebi.ac.uk/pdbsum/4g8z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4g8z ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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. | + | [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. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Dihydrofolate reductase|Dihydrofolate reductase]] | + | *[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dihydrofolate reductase]] | |
| - | [[Category: Human pneumocystis pneumonia agent]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cody, V]] | + | [[Category: Pneumocystis jirovecii]] |
| - | [[Category: K37s and f69n mutation]] | + | [[Category: Cody V]] |
| - | [[Category: Mutant pcdhfr inhibitor complex]]
| + | |
| - | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
| + | |
| - | [[Category: Tmp/nadph ligand]]
| + | |
| Structural highlights
Function
DYR_PNECA Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Publication Abstract from PubMed
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.
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cody V, Pace J, Queener SF, Adair OO, Gangjee A. Kinetic and Structural Analysis for Potent Antifolate Inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and Human Dihydrofolate Reductases and Their Active-Site Variants. Antimicrob Agents Chemother. 2013 Jun;57(6):2669-77. doi: 10.1128/AAC.00172-13., Epub 2013 Apr 1. PMID:23545530 doi:10.1128/AAC.00172-13
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