3nu0 - Revision history

OCA at 10:01, 14 February 2024

2024-02-14T10:01:15Z

←Older revision		Revision as of 10:01, 14 February 2024
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	<StructureSection load='3nu0' size='340' side='right'caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>		<StructureSection load='3nu0' size='340' side='right'caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.35Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ghc\|3ghc]], [[3ntz\|3ntz]]</div></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [https://pdbe.org/3nu0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [https://www.ebi.ac.uk/pdbsum/3nu0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nu0 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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [https://pdbe.org/3nu0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [https://www.ebi.ac.uk/pdbsum/3nu0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nu0 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 ==~~	+
-	Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (+/-)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH(3) substituents inhibited human (h) TS (IC(50)=0.26-0.8muM), but not hDHFR. Substitution of the 2-CH(3) with a 2-NH(2) increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC(50)=0.09-0.1muM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.	+
-		+
-	Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.,Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A Bioorg Med Chem. 2011 Apr 9. PMID:21550809<ref>PMID:21550809</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 3nu0" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==
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	__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: Cyclized inhibitor]]~~	+
-	~~[[Category: Oxidoreductase hdhfr-264-nadph]]~~	+
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]	+

OCA at 07:09, 12 May 2022

2022-05-12T07:09:29Z

←Older revision		Revision as of 07:09, 12 May 2022
Line 1:		Line 1:

	==Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors==		==Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors==
-	<StructureSection load='3nu0' size='340' side='right' caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>	+	<StructureSection load='3nu0' size='340' side='right'caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ghc\|3ghc]], [[3ntz\|3ntz]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ghc\|3ghc]], [[3ntz\|3ntz]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([~~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, DHFRP1 ([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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [~~http~~://pdbe.org/3nu0 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3nu0 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3nu0 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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [https://pdbe.org/3nu0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [https://www.ebi.ac.uk/pdbsum/3nu0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3nu0 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 ==
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	</div>		</div>
	<div class="pdbe-citations 3nu0" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3nu0" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dihydrofolate reductase 3D structures\|Dihydrofolate reductase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
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	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Cody, V]]		[[Category: Cody, V]]
	[[Category: Cyclized inhibitor]]		[[Category: Cyclized inhibitor]]
	[[Category: Oxidoreductase hdhfr-264-nadph]]		[[Category: Oxidoreductase hdhfr-264-nadph]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 08:35, 8 November 2017

2017-11-08T08:35:59Z

←Older revision		Revision as of 08:35, 8 November 2017
Line 23:		Line 23:
	</div>		</div>
	<div class="pdbe-citations 3nu0" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3nu0" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 17:48, 5 August 2016

2016-08-05T17:48:41Z

←Older revision		Revision as of 17:48, 5 August 2016
Line 1:		Line 1:
		+
	==Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors==		==Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors==
	<StructureSection load='3nu0' size='340' side='right' caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>		<StructureSection load='3nu0' size='340' side='right' caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ghc\|3ghc]], [[3ntz\|3ntz]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ghc\|3ghc]], [[3ntz\|3ntz]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([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, DHFRP1 ([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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [http://www.ebi.ac.uk/pdbsum/3nu0 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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [http://pdbe.org/3nu0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [http://www.ebi.ac.uk/pdbsum/3nu0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3nu0 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 3nu0" 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: Cyclized inhibitor]]		[[Category: Cyclized inhibitor]]
	[[Category: Oxidoreductase hdhfr-264-nadph]]		[[Category: Oxidoreductase hdhfr-264-nadph]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 07:10, 19 December 2014

2014-12-19T07:10:21Z

←Older revision		Revision as of 07:10, 19 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3nu0\| PDB=3nu0 \| SCENE= }}~~	+	==Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors==
-	===Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors===	+	<StructureSection load='3nu0' size='340' side='right' caption='[[3nu0]], [[Resolution\|resolution]] 1.35Å' scene=''>
-	{~~{ABSTRACT_PUBMED_21550809}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3nu0]] 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=3NU0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3NU0 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3TU:(2S)-2-(5-{[(2-AMINO-4-OXO-3,4-DIHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-5-YL)METHYL]AMINO}-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTANEDIOIC+ACID'>3TU</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3ghc\|3ghc]], [[3ntz\|3ntz]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHFR, DHFRP1 ([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=3nu0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3nu0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3nu0 RCSB], [http://www.ebi.ac.uk/pdbsum/3nu0 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 ==
		+	Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of ethyl 2-amino-4-methyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (+/-)-9 to ethyl 2-amino-4-methyl-1-benzothiophene-3-carboxylate 10 with 10% Pd/C was a key synthetic step. Compounds with 2-CH(3) substituents inhibited human (h) TS (IC(50)=0.26-0.8muM), but not hDHFR. Substitution of the 2-CH(3) with a 2-NH(2) increases hTS inhibition by more than 10-fold and also affords excellent hDHFR inhibition (IC(50)=0.09-0.1muM). This study shows that the tricyclic benzo[4,5]thieno[2,3-d]pyrimidine scaffold is highly conducive to single hTS or dual hTS-hDHFR inhibition depending on the 2-position substituents. The X-ray crystal structures of 6 and 7 with hDHFR reveal, for the first time, that tricyclics 6 and 7 bind with the benzo[4,5]thieno[2,3-d]pyrimidine ring in the folate binding mode with the thieno S mimicking the 4-amino of methotrexate.

-	~~==Disease==~~	+	Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.,Zhang X, Zhou X, Kisliuk RL, Piraino J, Cody V, Gangjee A Bioorg Med Chem. 2011 Apr 9. PMID:21550809<ref>PMID:21550809</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==~~	+
-	[[3nu0]] 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=3NU0 OCA].	+

	==See Also==		==See Also==
	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]		*[[Dihydrofolate reductase\|Dihydrofolate reductase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:021550809</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: Cyclized inhibitor]]		[[Category: Cyclized inhibitor]]
-	[[Category: Dihydrofolate reductase]]
	[[Category: Oxidoreductase hdhfr-264-nadph]]		[[Category: Oxidoreductase hdhfr-264-nadph]]
	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]		[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 02:46, 25 March 2013

2013-03-25T02:46:50Z

←Older revision		Revision as of 02:46, 25 March 2013
Line 1:		Line 1:
-	[[Image:3nu0.png\|left\|200px]]
-
	{{STRUCTURE_3nu0\| PDB=3nu0 \| SCENE= }}		{{STRUCTURE_3nu0\| PDB=3nu0 \| SCENE= }}
-
	===Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors===		===Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors===
		+	{{ABSTRACT_PUBMED_21550809}}

-	~~{{ABSTRACT_PUBMED_21550809}}~~	+	==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:021550809</ref><references group="xtra"/>	+	<ref group="xtra">PMID:021550809</ref><references group="xtra"/><references/>
	[[Category: Dihydrofolate reductase]]		[[Category: Dihydrofolate reductase]]
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]

OCA at 12:42, 20 October 2012

2012-10-20T12:42:36Z

←Older revision		Revision as of 12:42, 20 October 2012
Line 8:		Line 8:

	==About this Structure==		==About this Structure==
-	[[3nu0]] 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=3NU0 OCA].	+	[[3nu0]] 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=3NU0 OCA].

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

OCA at 09:36, 26 July 2012

2012-07-26T09:36:55Z

←Older revision		Revision as of 09:36, 26 July 2012
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	[[Image:3nu0.png\|left\|200px]]		[[Image:3nu0.png\|left\|200px]]

-	<!--
-	The line below this paragraph, containing "STRUCTURE_3nu0", 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.
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	{{STRUCTURE_3nu0\| PDB=3nu0 \| SCENE= }}		{{STRUCTURE_3nu0\| PDB=3nu0 \| SCENE= }}

	===Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors===		===Design, Synthesis, Biological Evaluation and X-ray Crystal Structure of Novel Classical 6,5,6-TricyclicBenzo[4,5]thieno[2,3-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors===

-
-	<!--
-	The line below this paragraph, {{ABSTRACT_PUBMED_21550809}}, adds the Publication Abstract to the page
-	(as it appears on PubMed at http://www.pubmed.gov), where 21550809 is the PubMed ID number.
-	-->
	{{ABSTRACT_PUBMED_21550809}}		{{ABSTRACT_PUBMED_21550809}}

	==About this Structure==		==About this Structure==
-	[[3nu0]] 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=3NU0 OCA].	+	[[3nu0]] 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=3NU0 OCA].
		+
		+	==See Also==
		+	*[[Dihydrofolate reductase\|Dihydrofolate reductase]]

	==Reference==		==Reference==

OCA at 05:32, 15 June 2011

2011-06-15T05:32:32Z

←Older revision		Revision as of 05:32, 15 June 2011
Line 1:		Line 1:
-	[[Image:3nu0.~~jpg~~\|left\|200px]]	+	[[Image:3nu0.png\|left\|200px]]

	<!--		<!--
Line 26:		Line 26:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Cody, V.]]		[[Category: Cody, V.]]
		+	[[Category: Cyclized inhibitor]]
		+	[[Category: Dihydrofolate reductase]]
		+	[[Category: Oxidoreductase hdhfr-264-nadph]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA: Protected "3nu0" [edit=sysop:move=sysop]

2011-05-25T05:37:30Z

Protected "3nu0" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:37, 25 May 2011