4g8z - Revision history

OCA at 15:41, 14 March 2024

2024-03-14T15:41:16Z

←Older revision		Revision as of 15:41, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<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>		<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" id="ligandDat"><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='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.75Å</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='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='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>
	</table>		</table>
	== Function ==		== Function ==
	[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.		[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;">
-	== 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<ref>PMID:23545530</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4g8z" 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>

OCA at 06:43, 26 October 2022

2022-10-26T06:43:10Z

←Older revision		Revision as of 06:43, 26 October 2022
Line 3:		Line 3:
	<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 ==
Line 22:		Line 20:

	==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~~]]	+

OCA at 07:51, 27 March 2019

2019-03-27T07:51:48Z

←Older revision		Revision as of 07:51, 27 March 2019
Line 1:		Line 1:

	==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==		==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==
-	<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/~~Pneji Pneji~~]. 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 [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>
	</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"><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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dyr\|1dyr]]</td></tr>
Line 28:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
-	[[Category: ~~Pneji~~]]	+	[[Category: Human pneumocystis pneumonia agent]]
		+	[[Category: Large Structures]]
	[[Category: Cody, V]]		[[Category: Cody, V]]
	[[Category: K37s and f69n mutation]]		[[Category: K37s and f69n mutation]]

OCA at 04:35, 5 August 2016

2016-08-05T04:35:56Z

←Older revision		Revision as of 04:35, 5 August 2016
Line 1:		Line 1:
		+
	==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==		==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==
	<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/~~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>	+	<table><tr><td colspan='2'>[[4g8z]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pneji Pneji]. 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>
	</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"><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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dyr\|1dyr]]</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='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://www.rcsb.org/pdb/explore.do?structureId=4g8z RCSB], [http://www.ebi.ac.uk/pdbsum/4g8z PDBsum]</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 ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4g8z" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 26:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
-	[[Category: ~~Pneumocystis jirovecii~~]]	+	[[Category: Pneji]]
	[[Category: Cody, V]]		[[Category: Cody, V]]
	[[Category: K37s and f69n mutation]]		[[Category: K37s and f69n mutation]]

OCA at 23:01, 24 December 2014

2014-12-24T23:01:11Z

←Older revision		Revision as of 23:01, 24 December 2014
Line 8:		Line 8:
	<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>		<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>
	</table>		</table>
		+	== 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.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 11:19, 21 December 2014

2014-12-21T11:19:50Z

←Older revision		Revision as of 11:19, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4g8z\| PDB=4g8z \| SCENE= }}~~	+	==pcDHFR K37S/F69N double mutant TMP NADPH ternary complex==
-	===pcDHFR K37S/F69N double mutant TMP NADPH ternary complex===	+	<StructureSection load='4g8z' size='340' side='right' caption='[[4g8z]], [[Resolution\|resolution]] 1.75Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23545530}}~~	+	== Structural highlights ==
		+	<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>
		+	</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>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1dyr\|1dyr]]</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://www.rcsb.org/pdb/explore.do?structureId=4g8z RCSB], [http://www.ebi.ac.uk/pdbsum/4g8z PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== 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.

-	~~==Function==~~	+	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>
-	~~[[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~~.	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[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].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023545530</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Pneumocystis jirovecii]]		[[Category: Pneumocystis jirovecii]]
-	[[Category: Cody, V.]]	+	[[Category: Cody, V]]
	[[Category: K37s and f69n mutation]]		[[Category: K37s and f69n mutation]]
	[[Category: Mutant pcdhfr inhibitor complex]]		[[Category: Mutant pcdhfr inhibitor complex]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
	[[Category: Tmp/nadph ligand]]		[[Category: Tmp/nadph ligand]]

OCA at 15:48, 19 June 2013

2013-06-19T15:48:44Z

←Older revision		Revision as of 15:48, 19 June 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4g8z\| PDB=4g8z \| SCENE= }}
		+	===pcDHFR K37S/F69N double mutant TMP NADPH ternary complex===
		+	{{ABSTRACT_PUBMED_23545530}}

-	~~The entry 4g8z is ON HOLD~~	+	==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.

-	~~Authors~~: ~~Cody, V~~.	+	==About this Structure==
		+	[[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].

-	~~Description~~: ~~pcDHFR K37S~~/~~F69N double mutant TMP NADPH ternary~~ complex	+	==Reference==
		+	<ref group="xtra">PMID:023545530</ref><references group="xtra"/><references/>
		+	[[Category: Dihydrofolate reductase]]
		+	[[Category: Pneumocystis jirovecii]]
		+	[[Category: Cody, V.]]
		+	[[Category: K37s and f69n mutation]]
		+	[[Category: Mutant pcdhfr inhibitor complex]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
		+	[[Category: Tmp/nadph ligand]]

OCA at 04:58, 8 August 2012

2012-08-08T04:58:50Z

←Older revision		Revision as of 04:58, 8 August 2012
Line 3:		Line 3:
	The entry 4g8z is ON HOLD		The entry 4g8z is ON HOLD

-	Authors: Cody, ~~Vivian~~	+	Authors: Cody, V.

	Description: pcDHFR K37S/F69N double mutant TMP NADPH ternary complex		Description: pcDHFR K37S/F69N double mutant TMP NADPH ternary complex

OCA: Protected "4g8z" [edit=sysop:move=sysop]

2012-08-01T05:31:18Z

Protected "4g8z" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:31, 1 August 2012

OCA: New page: '''Unreleased structure''' The entry 4g8z is ON HOLD Authors: Cody, Vivian Description: pcDHFR K37S/F69N double mutant TMP NADPH ternary complex

2012-08-01T05:31:17Z

New page: '''Unreleased structure''' The entry 4g8z is ON HOLD Authors: Cody, Vivian Description: pcDHFR K37S/F69N double mutant TMP NADPH ternary complex

New page

'''Unreleased structure'''

The entry 4g8z is ON HOLD

Authors: Cody, Vivian

Description: pcDHFR K37S/F69N double mutant TMP NADPH ternary complex