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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7alb]] is a 40 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=7ALB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ALB FirstGlance]. <br>
<table><tr><td colspan='2'>[[7alb]] is a 40 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=7ALB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ALB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PHE:PHENYLALANINE'>PHE</scene>, <scene name='pdbligand=QBQ:7-deaza-GTP'>QBQ</scene>, <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]] 1.979&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PHE:PHENYLALANINE'>PHE</scene>, <scene name='pdbligand=QBQ:7-deaza-GTP'>QBQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7alb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7alb OCA], [https://pdbe.org/7alb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7alb RCSB], [https://www.ebi.ac.uk/pdbsum/7alb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7alb 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=7alb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7alb OCA], [https://pdbe.org/7alb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7alb RCSB], [https://www.ebi.ac.uk/pdbsum/7alb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7alb ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
== Function ==
[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>  
[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;">
== 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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7alb" style="background-color:#fffaf0;"></div>


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

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