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7acc

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human GTP cyclohydrolase I feedback regulatory protein (GFRP)

Structural highlights

7acc is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.04Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GFRP_HUMAN Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chavan B, Gillbro JM, Rokos H, Schallreuter KU. GTP cyclohydrolase feedback regulatory protein controls cofactor 6-tetrahydrobiopterin synthesis in the cytosol and in the nucleus of epidermal keratinocytes and melanocytes. J Invest Dermatol. 2006 Nov;126(11):2481-9. Epub 2006 Jun 15. PMID:16778797 doi:http://dx.doi.org/5700425
↑ Ebenhoch R, Prinz S, Kaltwasser S, Mills DJ, Meinecke R, Rubbelke M, Reinert D, Bauer M, Weixler L, Zeeb M, Vonck J, Nar H. A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I. Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 2013473117. doi:, 10.1073/pnas.2013473117. PMID:33229582 doi:http://dx.doi.org/10.1073/pnas.2013473117

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7acc"

Categories: Homo sapiens | Large Structures | Ebenhoch R | Nar H

@@ Line 3: / Line 3: @@
 <StructureSection load='7acc' size='340' side='right'caption='[[7acc]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7acc]] is a 10 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=7ACC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7ACC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7acc]] is a 10 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=7ACC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ACC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</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]] 2.04&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCHFR, GFRP ([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=K:POTASSIUM+ION'>K</scene></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=7acc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7acc OCA], [http://pdbe.org/7acc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7acc RCSB], [http://www.ebi.ac.uk/pdbsum/7acc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7acc 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=7acc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7acc OCA], [https://pdbe.org/7acc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7acc RCSB], [https://www.ebi.ac.uk/pdbsum/7acc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7acc ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GFRP_HUMAN GFRP_HUMAN]] Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.<ref>PMID:16778797</ref>
+[https://www.uniprot.org/uniprot/GFRP_HUMAN GFRP_HUMAN] Mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase 1. This inhibition is reversed by L-phenylalanine.<ref>PMID:16778797</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ebenhoch, R]]
+[[Category: Ebenhoch R]]
-[[Category: Nar, H]]
+[[Category: Nar H]]
-[[Category: Gtp cyclohydrolase 1 feedback regulatory protein]]
-[[Category: Protein binding]]
-[[Category: Regulatory protein]]

7acc

From Proteopedia

Current revision

human GTP cyclohydrolase I feedback regulatory protein (GFRP)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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