3s3v - Revision history

OCA at 09:47, 1 March 2024

2024-03-01T09:47:18Z

←Older revision		Revision as of 09:47, 1 March 2024
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	<StructureSection load='3s3v' size='340' side='right'caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>		<StructureSection load='3s3v' size='340' side='right'caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3V FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.53Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>~~[[~~Related_structure~~\|~~Related:~~]]~~</b></td><td class="sblockDat"><div style='overflow: auto~~; ~~max-height: 3em;'>[[3n0h\|3n0h]]</div>~~</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TOP:TRIMETHOPRIM'>TOP</scene></td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>DHFR, pds5 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id=~~9606 HUMAN])</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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [https://pdbe.org/3s3v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [https://www.ebi.ac.uk/pdbsum/3s3v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3v 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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [https://pdbe.org/3s3v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [https://www.ebi.ac.uk/pdbsum/3s3v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3v ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>	+	[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>	+	[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	In order to produce a more potent replacement for trimethoprim (TMP) used as a therapy for Pneumocystis pneumonia and targets dihydrofolate reductase from Pneumocystis jirovecii (pjDHFR), it is necessary to understand the determinants of potency and selectivity against DHFR from the mammalian host and fungal pathogen cells. To this end, active site residues in human (h) DHFR were replaced with those from pjDHFR. Structural data are reported for two complexes of TMP with the double mutants Gln35Ser/Asn64Phe (Q35S/N64F) and Gln35Lys/Asn64Phe (Q35K/N64F) of hDHFR that unexpectedly show evidence for the binding of two molecules of TMP: one molecule that binds in the normal folate binding site and the second molecule that binds in a novel subpocket site such that the mutated residue Phe64 is involved in van der Waals contacts to the trimethoxyphenyl ring of the second TMP molecule. Kinetic data for the binding of TMP to hDHFR and pjDHFR reveal an 84-fold selectivity of TMP against pjDHFR (K(i) 49nM) compared to hDHFR (K(i) 4093nM). Two mutants that contain one substitution from pj- and one from the closely related Pneumocystis carinii DHFR (pcDHFR) (Q35K/N64F and Q35S/N64F) show K(i) values of 593 and 617nM, respectively; these K(i) values are well above both the K(i) for pjDHFR and are similar to pcDHFR (Q35K/N64F and Q35S/N64F) (305nM). These results suggest that active site residues 35 and 64 play key roles in determining selectivity for pneumocystis DHFR, but that other residues contribute to the unique binding of inhibitors to these enzymes.	+
-		+
-	Crystallographic analysis reveals a novel second binding site for trimethoprim in active site double mutants of human dihydrofolate reductase.,Cody V, Pace J, Piraino J, Queener SF J Struct Biol. 2011 Oct;176(1):52-9. Epub 2011 Jun 13. PMID:21684339<ref>PMID:21684339</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3s3v" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
Line 30:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Dihydrofolate reductase]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Cody, V]]	+	[[Category: Cody V]]
-	[[Category: Pace, J]]	+	[[Category: Pace J]]
-	[[Category: Piraino, J]]	+	[[Category: Piraino J]]
-	[[Category: Queener~~, S F]]~~	+	[[Category: Queener SF]]
-	~~[[Category: Novel second binding site]]~~	+
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]	+

OCA at 10:37, 22 June 2022

2022-06-22T10:37:12Z

←Older revision		Revision as of 10:37, 22 June 2022
Line 1:		Line 1:

	==human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim==		==human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim==
-	<StructureSection load='3s3v' size='340' side='right' caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>	+	<StructureSection load='3s3v' size='340' side='right'caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3S3V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S3V FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=SO4:SULFATE+ION'>SO4</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">[[3n0h\|3n0h]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3n0h\|3n0h]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, pds5 ([~~http~~://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, pds5 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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'>[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'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [~~http~~://pdbe.org/3s3v PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3s3v PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3v 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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [https://pdbe.org/3s3v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [https://www.ebi.ac.uk/pdbsum/3s3v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3v ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[~~http~~://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>	+	[[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[https://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>	+	[[https://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 25:

	==See Also==		==See Also==
-	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]	+	*[[Dihydrofolate reductase 3D structures\|Dihydrofolate reductase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
Line 32:		Line 32:
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Cody, V]]		[[Category: Cody, V]]
	[[Category: Pace, J]]		[[Category: Pace, J]]

OCA at 17:27, 4 August 2016

2016-08-04T17:27:33Z

←Older revision		Revision as of 17:27, 4 August 2016
Line 1:		Line 1:
		+
	==human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim==		==human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim==
	<StructureSection load='3s3v' size='340' side='right' caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>		<StructureSection load='3s3v' size='340' side='right' caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3V FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=SO4:SULFATE+ION'>SO4</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">[[3n0h\|3n0h]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3n0h\|3n0h]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, pds5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, pds5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [http://www.ebi.ac.uk/pdbsum/3s3v 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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [http://pdbe.org/3s3v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [http://www.ebi.ac.uk/pdbsum/3s3v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3s3v ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	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 3s3v" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 29:		Line 31:
	</StructureSection>		</StructureSection>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Cody, V]]		[[Category: Cody, V]]
	[[Category: Pace, J]]		[[Category: Pace, J]]

OCA at 10:39, 19 December 2014

2014-12-19T10:39:36Z

←Older revision		Revision as of 10:39, 19 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}~~	+	==human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim==
-	===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===	+	<StructureSection load='3s3v' size='340' side='right' caption='[[3s3v]], [[Resolution\|resolution]] 1.53Å' scene=''>
-	~~{{ABSTRACT_PUBMED_21684339}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S3V FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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">[[3n0h\|3n0h]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, pds5 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3s3v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s3v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s3v RCSB], [http://www.ebi.ac.uk/pdbsum/3s3v PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[http://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref> <ref>PMID:21310277</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref> <ref>PMID:12096917</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	In order to produce a more potent replacement for trimethoprim (TMP) used as a therapy for Pneumocystis pneumonia and targets dihydrofolate reductase from Pneumocystis jirovecii (pjDHFR), it is necessary to understand the determinants of potency and selectivity against DHFR from the mammalian host and fungal pathogen cells. To this end, active site residues in human (h) DHFR were replaced with those from pjDHFR. Structural data are reported for two complexes of TMP with the double mutants Gln35Ser/Asn64Phe (Q35S/N64F) and Gln35Lys/Asn64Phe (Q35K/N64F) of hDHFR that unexpectedly show evidence for the binding of two molecules of TMP: one molecule that binds in the normal folate binding site and the second molecule that binds in a novel subpocket site such that the mutated residue Phe64 is involved in van der Waals contacts to the trimethoxyphenyl ring of the second TMP molecule. Kinetic data for the binding of TMP to hDHFR and pjDHFR reveal an 84-fold selectivity of TMP against pjDHFR (K(i) 49nM) compared to hDHFR (K(i) 4093nM). Two mutants that contain one substitution from pj- and one from the closely related Pneumocystis carinii DHFR (pcDHFR) (Q35K/N64F and Q35S/N64F) show K(i) values of 593 and 617nM, respectively; these K(i) values are well above both the K(i) for pjDHFR and are similar to pcDHFR (Q35K/N64F and Q35S/N64F) (305nM). These results suggest that active site residues 35 and 64 play key roles in determining selectivity for pneumocystis DHFR, but that other residues contribute to the unique binding of inhibitors to these enzymes.

-	~~==Disease==~~	+	Crystallographic analysis reveals a novel second binding site for trimethoprim in active site double mutants of human dihydrofolate reductase.,Cody V, Pace J, Piraino J, Queener SF J Struct Biol. 2011 Oct;176(1):52-9. Epub 2011 Jun 13. PMID:21684339<ref>PMID:21684339</ref>
-	~~[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects~~ in ~~DHFR are the cause~~ of ~~megaloblastic anemia due to~~ dihydrofolate reductase ~~deficiency (DHFRD) [MIM:[http://omim~~.~~org/entry/613839 613839]]. DHFRD is an inborn error of metabolism~~, ~~characterized by megaloblastic anemia and/or pancytopenia~~, ~~severe cerebral folate deficiency~~, ~~and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms~~, ~~ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms~~.~~<ref>~~PMID:~~21310276</ref>~~<ref>PMID:~~21310277~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~/~~/www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to~~ the ~~de novo mitochondrial thymidylate biosynthesis pathway~~. ~~Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis~~. ~~Binds its own mRNA and that~~ of ~~DHFRL1~~.<~~ref~~>~~PMID:21876188~~</~~ref~~>~~<ref>PMID:12096917</ref>~~	+	</div>
-		+
-	~~==About this Structure==~~	+
-	[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].	+

	==See Also==		==See Also==
	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]		*[[Dihydrofolate reductase\|Dihydrofolate reductase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:021684339</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Cody, V.]]	+	[[Category: Cody, V]]
-	[[Category: Pace, J.]]	+	[[Category: Pace, J]]
-	[[Category: Piraino, J.]]	+	[[Category: Piraino, J]]
-	[[Category: Queener, S F.]]	+	[[Category: Queener, S F]]
	[[Category: Novel second binding site]]		[[Category: Novel second binding site]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 23:15, 24 March 2013

2013-03-24T23:15:16Z

←Older revision		Revision as of 23:15, 24 March 2013
Line 1:		Line 1:
-	[[Image:3s3v.png\|left\|200px]]
-
	{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}		{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}
-
	===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===		===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===
		+	{{ABSTRACT_PUBMED_21684339}}

-	~~{{ABSTRACT_PUBMED_21684339}}~~	+	==Disease==
		+	[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Defects in DHFR are the cause of megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD) [MIM:[http://omim.org/entry/613839 613839]]. DHFRD is an inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.<ref>PMID:21310276</ref><ref>PMID:21310277</ref>
		+
		+	==Function==
		+	[[http://www.uniprot.org/uniprot/DYR_HUMAN DYR_HUMAN]] Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.<ref>PMID:21876188</ref><ref>PMID:12096917</ref>

	==About this Structure==		==About this Structure==
Line 14:		Line 16:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:021684339</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021684339</ref><references group="xtra"/><references/>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]

OCA at 16:07, 20 October 2012

2012-10-20T16:07:55Z

←Older revision		Revision as of 16:07, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3s3v]] is a 1 chain structure ~~of [[Dihydrofolate reductase]]~~ with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].	+	[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].

	==See Also==		==See Also==

OCA at 20:41, 26 July 2012

2012-07-26T20:41:53Z

←Older revision		Revision as of 20:41, 26 July 2012
Line 1:		Line 1:
-	[[Image:3s3v.~~jpg~~\|left\|200px]]	+	[[Image:3s3v.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3s3v", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}		{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}

	===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===		===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21684339}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21684339 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_21684339}}		{{ABSTRACT_PUBMED_21684339}}

	==About this Structure==		==About this Structure==
-	[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].	+	[[3s3v]] is a 1 chain structure of [[Dihydrofolate reductase]] with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].
		+
		+	==See Also==
		+	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]

	==Reference==		==Reference==

OCA at 05:33, 28 September 2011

2011-09-28T05:33:51Z

←Older revision		Revision as of 05:33, 28 September 2011
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3s3v.jpg\|left\|200px]]

-	The ~~entry 3s3v~~ is ~~ON HOLD~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3s3v", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3s3v\| PDB=3s3v \| SCENE= }}

-	~~Authors: Cody, V., Pace, J., Piraino, J., Queener, S.F.~~	+	===human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim===

-	~~Description~~: ~~human dihydrofolate reductase Q35K~~/~~N64F double mutant binary complex~~ with ~~trimethoprim~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_21684339}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 21684339 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_21684339}}
		+
		+	==About this Structure==
		+	[[3s3v]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S3V OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:021684339</ref><references group="xtra"/>
		+	[[Category: Dihydrofolate reductase]]
		+	[[Category: Homo sapiens]]
		+	[[Category: Cody, V.]]
		+	[[Category: Pace, J.]]
		+	[[Category: Piraino, J.]]
		+	[[Category: Queener, S F.]]
		+	[[Category: Novel second binding site]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 05:54, 15 June 2011

2011-06-15T05:54:04Z

←Older revision		Revision as of 05:54, 15 June 2011
Line 3:		Line 3:
	The entry 3s3v is ON HOLD		The entry 3s3v is ON HOLD

-	Authors: Cody, V., Pace, J, Piraino, J, Queener, S.F.	+	Authors: Cody, V., Pace, J., Piraino, J., Queener, S.F.

	Description: human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim		Description: human dihydrofolate reductase Q35K/N64F double mutant binary complex with trimethoprim

OCA: Protected "3s3v" [edit=sysop:move=sysop]

2011-05-25T05:16:03Z

Protected "3s3v" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:16, 25 May 2011