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- PDB-6z87: human GTP cyclohydrolase I -

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Basic information

Entry
Database: PDB / ID: 6z87
Titlehuman GTP cyclohydrolase I
ComponentsGTP cyclohydrolase 1GTP cyclohydrolase I
KeywordsHYDROLASE / GTP cyclohydrolase I / EC:3.5.4.16 / Tetrahydrobiopterin (BH4) synthesis / Cytosol / Zinc Ion Binding / Hydrolase Activity / Metal Ion Binding / Nucleotide Binding / allosteric inhibitor
Function / homology
Function and homology information


pteridine-containing compound biosynthetic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / : / neuromuscular process controlling posture / regulation of removal of superoxide radicals / GTP-dependent protein binding / tetrahydrobiopterin biosynthetic process / neuron projection terminus ...pteridine-containing compound biosynthetic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / : / neuromuscular process controlling posture / regulation of removal of superoxide radicals / GTP-dependent protein binding / tetrahydrobiopterin biosynthetic process / neuron projection terminus / mitogen-activated protein kinase binding / dopamine biosynthetic process / negative regulation of cardiac muscle cell apoptotic process / response to pain / positive regulation of heart rate / response to type II interferon / negative regulation of cellular senescence / response to tumor necrosis factor / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / tetrahydrofolate biosynthetic process / positive regulation of telomere maintenance via telomerase / negative regulation of blood pressure / nitric oxide biosynthetic process / positive regulation of nitric-oxide synthase activity / regulation of blood pressure / vasodilation / positive regulation of neuron apoptotic process / cytoplasmic vesicle / protein-containing complex assembly / nuclear membrane / response to lipopolysaccharide / GTPase activity / calcium ion binding / protein-containing complex binding / GTP binding / protein homodimerization activity / protein-containing complex / mitochondrion / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
GTP cyclohydrolase I signature 2. / GTP cyclohydrolase I / GTP cyclohydrolase I, conserved site / GTP cyclohydrolase I domain / GTP cyclohydrolase I, N-terminal domain / GTP cyclohydrolase I / GTP cyclohydrolase I signature 1. / GTP cyclohydrolase I, C-terminal/NADPH-dependent 7-cyano-7-deazaguanine reductase
Similarity search - Domain/homology
GTP cyclohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.564 Å
AuthorsEbenhoch, R. / Nar, H.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I.
Authors: Rebecca Ebenhoch / Simone Prinz / Susann Kaltwasser / Deryck J Mills / Robert Meinecke / Martin Rübbelke / Dirk Reinert / Margit Bauer / Lisa Weixler / Markus Zeeb / Janet Vonck / Herbert Nar /
Abstract: Guanosine triphosphate (GTP) cyclohydrolase I (GCH1) catalyzes the conversion of GTP to dihydroneopterin triphosphate (H2NTP), the initiating step in the biosynthesis of tetrahydrobiopterin (BH4). ...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.
History
DepositionJun 2, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
E: GTP cyclohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,95210
Polymers126,6255
Non-polymers3275
Water1,54986
1
A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
E: GTP cyclohydrolase 1
hetero molecules

A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
E: GTP cyclohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)253,90320
Polymers253,24910
Non-polymers65410
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_555-y,-x,-z+1/61
Buried area41900 Å2
ΔGint-607 kcal/mol
Surface area67250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)109.877, 109.877, 387.247
Angle α, β, γ (deg.)90, 90, 120
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein
GTP cyclohydrolase 1 / GTP cyclohydrolase I / GTP cyclohydrolase I / GTP-CH-I


Mass: 25324.920 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCH1, DYT5, GCH / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P30793, GTP cyclohydrolase I
#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.26 Å3/Da / Density % sol: 62.32 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 1.26 M Ammonium Sulfate, 0.1 M TRIS pH 8.5 and 0.2 M Lithium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 2.564→95.156 Å / Num. obs: 44678 / % possible obs: 93.6 % / Redundancy: 18.6 % / CC1/2: 0.997 / Net I/σ(I): 13.7
Reflection shellResolution: 2.564→2.904 Å / Mean I/σ(I) obs: 1.9 / Num. unique obs: 21546 / CC1/2: 0.67 / % possible all: 77.2

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FB1

1fb1


Resolution: 2.564→95.156 Å / Cor.coef. Fo:Fc: 0.911 / Cor.coef. Fo:Fc free: 0.903 / Cross valid method: THROUGHOUT / SU Rfree Blow DPI: 0.39
RfactorNum. reflection% reflectionSelection details
Rfree0.2461 1370 -RANDOM
Rwork0.2274 ---
obs0.2283 27253 59.8 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-1.032 Å20 Å20 Å2
2--1.032 Å20 Å2
3----2.0639 Å2
Refine analyzeLuzzati coordinate error obs: 0.44 Å
Refinement stepCycle: LAST / Resolution: 2.564→95.156 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7366 0 5 86 7457
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0077484HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9210101HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2702SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1259HARMONIC5
X-RAY DIFFRACTIONt_it7484HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion993SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact5767SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion17.57
LS refinement shellResolution: 2.564→2.76 Å / Num. reflection Rfree: 26
Refinement TLS params.

Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.9348-2.29390.18419.9283-0.56761.75440.0685-0.63810.2035-0.6381-0.1478-0.04210.2035-0.04210.07930.0082-0.0137-0.0354-0.09470.0639-0.1575-51.424633.34326.9024
22.3806-1.2545-3.32333.30543.58939.34950.1282-0.33490.0001-0.3349-0.2331-0.86970.0001-0.86970.1049-0.1828-0.0358-0.00840.06130.0406-0.1142-69.642324.249933.1696
32.57-0.36092.72031.8532-0.95738.16560.1065-0.2210.1546-0.2210.003-0.55050.1546-0.5505-0.1096-0.0103-0.14790.0388-0.17880.0824-0.0859-53.18842.146848.9895
412.43681.69781.48133.10080.52561.95760.06790.00650.54190.00650.0247-0.17930.5419-0.1793-0.09260.05840.08620.0102-0.27060.0558-0.144-24.8717-2.807733.9479
51.69452.5887-0.51846.9098-1.58911.95040.0601-0.13750.2538-0.1375-0.13910.06730.25380.06730.079-0.01870.00620.0389-0.0684-0.0092-0.1021-23.860516.49258.0375
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A58 - 249
2X-RAY DIFFRACTION1{ A|* }A300
3X-RAY DIFFRACTION2{ B|* }B57 - 249
4X-RAY DIFFRACTION2{ B|* }B300
5X-RAY DIFFRACTION3{ C|* }C57 - 249
6X-RAY DIFFRACTION3{ C|* }C300
7X-RAY DIFFRACTION4{ D|* }D58 - 249
8X-RAY DIFFRACTION4{ D|* }D300
9X-RAY DIFFRACTION5{ E|* }E58 - 249
10X-RAY DIFFRACTION5{ E|* }E300

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