6z87 - Revision history

OCA at 13:43, 24 January 2024

OCA — Wed, 24 Jan 2024 13:43:34 GMT

←Older revision		Revision as of 13:43, 24 January 2024
Line 3:		Line 3:
	<StructureSection load='6z87' size='340' side='right'caption='[[6z87]], [[Resolution\|resolution]] 2.56Å' scene=''>		<StructureSection load='6z87' size='340' side='right'caption='[[6z87]], [[Resolution\|resolution]] 2.56Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6z87]] is a 5 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=6Z87 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6Z87 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6z87]] is a 5 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=6Z87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z87 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.564Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>GCH1, DYT5, GCH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id=~~9606 HUMAN])</td~~><~~/tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-	~~<tr id~~='~~activity'><td class~~=~~"sblockLbl"><b>Activity~~:~~</b></td><td class="sblockDat"><span class='plainlinks~~'>~~[http://en.wikipedia.org/wiki/GTP_cyclohydrolase_I GTP cyclohydrolase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.16 3.5.4.16]~~ </~~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=6z87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z87 OCA], [https://pdbe.org/6z87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z87 RCSB], [https://www.ebi.ac.uk/pdbsum/6z87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z87 ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6z87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z87 OCA], [~~http~~://pdbe.org/6z87 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6z87 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6z87 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6z87 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:[~~http~~://omim.org/entry/233910 233910]]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.<ref>PMID:7501255</ref> <ref>PMID:9667588</ref> Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:[~~http~~://omim.org/entry/128230 128230]]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.<ref>PMID:7501255</ref> <ref>PMID:7874165</ref> <ref>PMID:8957022</ref> <ref>PMID:8852666</ref> <ref>PMID:9120469</ref> <ref>PMID:9328244</ref> <ref>PMID:9778264</ref> <ref>PMID:10987649</ref> <ref>PMID:10582612</ref> <ref>PMID:10208576</ref> <ref>PMID:10076897</ref> <ref>PMID:10825351</ref> <ref>PMID:11113234</ref> <ref>PMID:12391354</ref> <ref>PMID:17101830</ref>	+	[https://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:[https://omim.org/entry/233910 233910]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.<ref>PMID:7501255</ref> <ref>PMID:9667588</ref> Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:[https://omim.org/entry/128230 128230]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.<ref>PMID:7501255</ref> <ref>PMID:7874165</ref> <ref>PMID:8957022</ref> <ref>PMID:8852666</ref> <ref>PMID:9120469</ref> <ref>PMID:9328244</ref> <ref>PMID:9778264</ref> <ref>PMID:10987649</ref> <ref>PMID:10582612</ref> <ref>PMID:10208576</ref> <ref>PMID:10076897</ref> <ref>PMID:10825351</ref> <ref>PMID:11113234</ref> <ref>PMID:12391354</ref> <ref>PMID:17101830</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.<ref>PMID:8068008</ref> <ref>PMID:9445252</ref> <ref>PMID:12176133</ref> <ref>PMID:16338639</ref> <ref>PMID:17057711</ref>	+	[https://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.<ref>PMID:8068008</ref> <ref>PMID:9445252</ref> <ref>PMID:12176133</ref> <ref>PMID:16338639</ref> <ref>PMID:17057711</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 6z87" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6z87" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Cyclohydrolase 3D structures\|Cyclohydrolase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~GTP cyclohydrolase I]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ebenhoch, R]]	+	[[Category: Ebenhoch R]]
-	[[Category: Nar, H]]	+	[[Category: Nar H]]
-	~~[[Category: Allosteric inhibitor]]~~	+
-	~~[[Category: Cytosol]]~~	+
-	~~[[Category: Ec:3 5.4 16]]~~	+
-	~~[[Category: Gtp cyclohydrolase i]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase activity]]~~	+
-	~~[[Category: Metal ion binding]]~~	+
-	~~[[Category: Nucleotide binding]]~~	+
-	~~[[Category: Zinc ion binding~~]]	+

OCA at 11:00, 24 December 2020

OCA — Thu, 24 Dec 2020 11:00:24 GMT

←Older revision		Revision as of 11:00, 24 December 2020
Line 1:		Line 1:

	==human GTP cyclohydrolase I==		==human GTP cyclohydrolase I==
-	<StructureSection load='6z87' size='340' side='right'caption='[[6z87]]' scene=''>	+	<StructureSection load='6z87' size='340' side='right'caption='[[6z87]], [[Resolution\|resolution]] 2.56Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z87 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z87 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6z87]] is a 5 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=6Z87 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z87 FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6z87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z87 OCA], [http://pdbe.org/6z87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z87 RCSB], [http://www.ebi.ac.uk/pdbsum/6z87 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z87 ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GCH1, DYT5, GCH ([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/GTP_cyclohydrolase_I GTP cyclohydrolase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.4.16 3.5.4.16] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6z87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z87 OCA], [http://pdbe.org/6z87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z87 RCSB], [http://www.ebi.ac.uk/pdbsum/6z87 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z87 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Defects in GCH1 are the cause of GTP cyclohydrolase 1 deficiency (GCH1D) [MIM:[http://omim.org/entry/233910 233910]]; also known as atypical severe phenylketonuria due to GTP cyclohydrolase I deficiency;. GCH1D is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. It is also responsible for defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia type 5 (dystonia-parkinsonism with diurnal fluctuation). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.<ref>PMID:7501255</ref> <ref>PMID:9667588</ref> Defects in GCH1 are the cause of dystonia type 5 (DYT5) [MIM:[http://omim.org/entry/128230 128230]]; also known as progressive dystonia with diurnal fluctuation, autosomal dominant Segawa syndrome or dystonia-parkinsonism with diurnal fluctuation. DYT5 is a DOPA-responsive dystonia. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT5 typically presents in childhood with walking problems due to dystonia of the lower limbs and worsening of the dystonia towards the evening. It is characterized by postural and motor disturbances showing marked diurnal fluctuation. Torsion of the trunk is unusual. Symptoms are alleviated after sleep and aggravated by fatigue and excercise. There is a favorable response to L-DOPA without side effects.<ref>PMID:7501255</ref> <ref>PMID:7874165</ref> <ref>PMID:8957022</ref> <ref>PMID:8852666</ref> <ref>PMID:9120469</ref> <ref>PMID:9328244</ref> <ref>PMID:9778264</ref> <ref>PMID:10987649</ref> <ref>PMID:10582612</ref> <ref>PMID:10208576</ref> <ref>PMID:10076897</ref> <ref>PMID:10825351</ref> <ref>PMID:11113234</ref> <ref>PMID:12391354</ref> <ref>PMID:17101830</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/GCH1_HUMAN GCH1_HUMAN]] Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs). May be involved in dopamine synthesis. May modify pain sensitivity and persistence. Isoform GCH-1 is the functional enzyme, the potential function of the enzymatically inactive isoforms remains unknown.<ref>PMID:8068008</ref> <ref>PMID:9445252</ref> <ref>PMID:12176133</ref> <ref>PMID:16338639</ref> <ref>PMID:17057711</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). Besides other roles, BH4 functions as cofactor in neurotransmitter biosynthesis. The BH4 biosynthetic pathway and GCH1 have been identified as promising targets to treat pain disorders in patients. The function of mammalian GCH1s is regulated by a metabolic sensing mechanism involving a regulator protein, GCH1 feedback regulatory protein (GFRP). GFRP binds to GCH1 to form inhibited or activated complexes dependent on availability of cofactor ligands, BH4 and phenylalanine, respectively. We determined high-resolution structures of human GCH1-GFRP complexes by cryoelectron microscopy (cryo-EM). Cryo-EM revealed structural flexibility of specific and relevant surface lining loops, which previously was not detected by X-ray crystallography due to crystal packing effects. Further, we studied allosteric regulation of isolated GCH1 by X-ray crystallography. Using the combined structural information, we are able to obtain a comprehensive picture of the mechanism of allosteric regulation. Local rearrangements in the allosteric pocket upon BH4 binding result in drastic changes in the quaternary structure of the enzyme, leading to a more compact, tense form of the inhibited protein, and translocate to the active site, leading to an open, more flexible structure of its surroundings. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by saturation transfer difference NMR (STD-NMR) and site-directed mutagenesis. We propose a dissociation rate controlled mechanism of allosteric, noncompetitive inhibition.
		+
		+	A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I.,Ebenhoch R, Prinz S, Kaltwasser S, Mills DJ, Meinecke R, Rubbelke M, Reinert D, Bauer M, Weixler L, Zeeb M, Vonck J, Nar H Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 2013473117. doi:, 10.1073/pnas.2013473117. PMID:33229582<ref>PMID:33229582</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6z87" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: GTP cyclohydrolase I]]
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ebenhoch R]]	+	[[Category: Ebenhoch, R]]
-	[[Category: Nar H]]	+	[[Category: Nar, H]]
		+	[[Category: Allosteric inhibitor]]
		+	[[Category: Cytosol]]
		+	[[Category: Ec:3 5.4 16]]
		+	[[Category: Gtp cyclohydrolase i]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase activity]]
		+	[[Category: Metal ion binding]]
		+	[[Category: Nucleotide binding]]
		+	[[Category: Zinc ion binding]]

OCA at 06:38, 9 December 2020

OCA — Wed, 09 Dec 2020 06:38:21 GMT

←Older revision		Revision as of 06:38, 9 December 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6z87 ~~is ON HOLD~~	+	==human GTP cyclohydrolase I==
-		+	<StructureSection load='6z87' size='340' side='right'caption='[[6z87]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z87 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z87 FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6z87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z87 OCA], [http://pdbe.org/6z87 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z87 RCSB], [http://www.ebi.ac.uk/pdbsum/6z87 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z87 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Ebenhoch R]]
		+	[[Category: Nar H]]

OCA: Protected "6z87" [edit=sysop:move=sysop]

OCA — Wed, 10 Jun 2020 05:09:49 GMT

Protected "6z87" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:09, 10 June 2020

OCA: New page: '''Unreleased structure''' The entry 6z87 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 10 Jun 2020 05:09:47 GMT

New page: '''Unreleased structure''' The entry 6z87 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6z87 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]