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- PDB-6z86: human GTP cyclohydrolase I in complex with 7-deaza-GTP -

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Basic information

Entry
Database: PDB / ID: 6z86
Titlehuman GTP cyclohydrolase I in complex with 7-deaza-GTP
ComponentsGTP cyclohydrolase 1
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 / dihydrobiopterin metabolic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / neuromuscular process controlling posture / GTP-dependent protein binding / regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / neuron projection terminus ...pteridine-containing compound biosynthetic process / dihydrobiopterin metabolic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / neuromuscular process controlling posture / GTP-dependent protein binding / regulation of removal of superoxide radicals / 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 / nitric oxide biosynthetic process / negative regulation of blood pressure / 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 / cytoplasm / cytosol
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
7-deaza-GTP / GTP cyclohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.206 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
F: GTP cyclohydrolase 1
G: GTP cyclohydrolase 1
H: GTP cyclohydrolase 1
I: GTP cyclohydrolase 1
J: GTP cyclohydrolase 1
K: GTP cyclohydrolase 1
L: GTP cyclohydrolase 1
M: GTP cyclohydrolase 1
N: GTP cyclohydrolase 1
O: GTP cyclohydrolase 1
P: GTP cyclohydrolase 1
Q: GTP cyclohydrolase 1
R: GTP cyclohydrolase 1
S: GTP cyclohydrolase 1
T: GTP cyclohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)518,25060
Polymers506,49820
Non-polymers11,75240
Water11,458636
1
A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
O: GTP cyclohydrolase 1
P: GTP cyclohydrolase 1
Q: GTP cyclohydrolase 1
R: GTP cyclohydrolase 1
S: GTP cyclohydrolase 1
T: GTP cyclohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)259,12530
Polymers253,24910
Non-polymers5,87620
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area50380 Å2
ΔGint-610 kcal/mol
Surface area59520 Å2
MethodPISA
2
E: GTP cyclohydrolase 1
F: GTP cyclohydrolase 1
G: GTP cyclohydrolase 1
H: GTP cyclohydrolase 1
I: GTP cyclohydrolase 1
J: GTP cyclohydrolase 1
K: GTP cyclohydrolase 1
L: GTP cyclohydrolase 1
M: GTP cyclohydrolase 1
N: GTP cyclohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)259,12530
Polymers253,24910
Non-polymers5,87620
Water18010
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area50670 Å2
ΔGint-603 kcal/mol
Surface area58930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)87.861, 88.595, 163.567
Angle α, β, γ (deg.)85.22, 88.91, 83.55
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 25324.920 Da / Num. of mol.: 20
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.: 20 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-QBQ / 7-deaza-GTP / [[(2~{R},3~{S},4~{R},5~{R})-5-(2-azanyl-4-oxidanylidene-3~{H}-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate


Mass: 522.192 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C11H17N4O14P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 636 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.93 Å3/Da / Density % sol: 58.04 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M Morpheus Buffer 1, 30 % EDO_P8K and Morpheus ethylene glycols (Morpheus HT-96; E10; Molecular Dimensions)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99988 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99988 Å / Relative weight: 1
ReflectionResolution: 2.206→87.739 Å / Num. obs: 142765 / % possible obs: 89.7 % / Redundancy: 1.8 % / Rmerge(I) obs: 0.045 / Rsym value: 0.045 / Net I/σ(I): 6.2
Reflection shellResolution: 2.206→2.457 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.337 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 7139 / Rsym value: 0.337 / % possible all: 62.4

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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: 2.206→162.99 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.926 / SU R Cruickshank DPI: 0.651 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.559 / SU Rfree Blow DPI: 0.248 / SU Rfree Cruickshank DPI: 0.257
RfactorNum. reflection% reflectionSelection details
Rfree0.208 2913 -RANDOM
Rwork0.1827 ---
obs0.1832 142496 57.9 %-
Displacement parametersBiso mean: 48.76 Å2
Baniso -1Baniso -2Baniso -3
1--1.8009 Å22.124 Å2-2.67 Å2
2--4.0389 Å2-5.0943 Å2
3----2.2381 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2.206→162.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms30039 0 660 636 31335
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00831217HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0542314HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d11338SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes5476HARMONIC5
X-RAY DIFFRACTIONt_it31217HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion4134SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact23732SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.24
X-RAY DIFFRACTIONt_other_torsion16.85
LS refinement shellResolution: 2.21→2.38 Å /
RfactorNum. reflection
Rfree0.2311 56
Rwork0.2097 -
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)
13.1639-0.2077-0.2010.52280.24881.2386-0.187-0.0874-0.3198-0.0874-0.04230.1047-0.31980.10470.2293-0.03960.0268-0.1067-0.1126-0.20070.0783-18.56672.03939.0807
21.35780.2370.17780.35730.08771.939-0.09960.0878-0.05070.08780.15110.4909-0.05070.4909-0.0515-0.1447-0.0024-0.01680.1188-0.0124-0.074635.1784-0.7086-65.2637
32.4967-0.0939-1.2480.66990.53043.26320.01510.13290.77310.13290.04180.31770.77310.3177-0.05680.05750.1236-0.07-0.1560.0398-0.037120.4509-23.8546-69.1222
42.549-0.26951.04810.69490.08441.1162-0.05890.17340.16160.17340.068-0.12060.1616-0.1206-0.0091-0.032-0.00910.00950.04440.0125-0.11749.8629-0.1873-50.1369
52.54490.56940.84310.90210.54781.7357-0.1043-0.4694-0.7029-0.4694-0.03990.0041-0.70290.00410.14410.15080.0687-0.0737-0.20820.1263-0.0171-1.850627.179-89.3137
62.3662-0.6433-0.46170.9290.42771.243-0.0092-0.047-0.4271-0.047-0.01690.2199-0.42710.21990.0261-0.0112-0.08410.0046-0.0876-0.0719-0.007315.064224.3578-61.8515
70.799-0.1551-0.02971.4687-0.69712.3521-0.0107-0.17140.2415-0.17140.03810.8020.24150.802-0.0273-0.14590.07090.03960.1665-0.122-0.100230.6816-13.3774-94.6632
81.07960.59510.11891.30550.81041.43870.00060.0727-0.12390.0727-0.1532-0.4443-0.1239-0.44430.1526-0.08640.0786-0.00320.0172-0.1038-0.0068-12.807415.8658-66.5096
90.80410.17260.63070.3454-0.24452.68990.1102-0.02010.4283-0.0201-0.0467-0.16180.4283-0.1618-0.06340.0353-0.0337-0.0158-0.0419-0.121-0.07324.6751-22.403-96.8826
101.01240.1626-0.54240.23780.72141.9659-0.03430.072-0.01670.0720.11120.2612-0.01670.2612-0.0769-0.08250.0197-0.07310.0872-0.0789-0.08264.5181-20.108712.8649
110.74090.21750.06191.88490.82461.29670.0333-0.316-0.2715-0.316-0.01680.209-0.27150.209-0.01650.018-0.0651-0.00630.11970.0105-0.22397.90833.6187-109.3289
121.0024-0.35360.29081.5483-0.60790.9258-0.0414-0.10870.1325-0.1087-0.0222-0.30830.1325-0.30830.0636-0.0815-0.0194-0.02690.0464-0.0726-0.0452-44.3801-31.3959-19.2992
131.0550.11860.14772.32470.08241.331-0.053-0.1776-0.0557-0.1776-0.164-0.4902-0.0557-0.49020.217-0.11280.0553-0.10110.1058-0.0649-0.0938-15.78581.93-95.0421
141.96810.37370.55540.6069-0.02581.4498-0.1277-0.1143-0.3338-0.1143-0.0631-0.0448-0.3338-0.04480.1908-0.00440.0619-0.0994-0.11090.02450.0334-33.628-3.9186-18.6977
151.0786-0.0163-0.12622.26820.42360.63450.0256-0.2046-0.0169-0.2046-0.03050.1429-0.01690.14290.0049-0.02850.0083-0.01250.0269-0.0595-0.1018-20.0037-29.9142-32.2639
161.92040.29910.57840.44310.04241.09150.01330.13940.15790.1394-0.0303-0.29790.1579-0.29790.0171-0.0843-0.0404-0.00380.1927-0.1241-0.1779-21.6795-19.380426.3498
170.9702-0.38090.3271.072-0.56651.92480.0017-0.06710.1732-0.06710.02670.44720.17320.4472-0.0284-0.07970.1014-0.01140.0344-0.0775-0.03223.7399-39.8712-12.8088
181.57630.79810.45541.49210.63560.5379-0.07610.08620.00530.0862-0.171-0.45220.0053-0.45220.2471-0.12670.1011-0.02390.1198-0.1948-0.0393-44.7637-10.89765.5963
192.6897-0.3255-0.69680.85680.46261.58080.0340.26160.57580.2616-0.01560.15140.57580.1514-0.01840.05630.0518-0.0657-0.060.0903-0.1016-6.6598-45.390414.2912
200.92250.3340.2910.53440.1582.63830.09440.04720.50460.0472-0.0645-0.04680.5046-0.0468-0.02990.06340.01390.017-0.1728-0.08120.0283-20.7352-52.9556-14.0488
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ N|* }N58 - 250
2X-RAY DIFFRACTION1{ N|* }N300 - 401
3X-RAY DIFFRACTION2{ A|* }A58 - 249
4X-RAY DIFFRACTION2{ A|* }A300 - 401
5X-RAY DIFFRACTION3{ O|* }O60 - 250
6X-RAY DIFFRACTION3{ O|* }O300 - 401
7X-RAY DIFFRACTION4{ B|* }B59 - 248
8X-RAY DIFFRACTION4{ B|* }B300 - 401
9X-RAY DIFFRACTION5{ P|* }P60 - 248
10X-RAY DIFFRACTION5{ P|* }P300 - 401
11X-RAY DIFFRACTION6{ C|* }C58 - 248
12X-RAY DIFFRACTION6{ C|* }C300 - 401
13X-RAY DIFFRACTION7{ Q|* }Q59 - 248
14X-RAY DIFFRACTION7{ Q|* }Q300 - 401
15X-RAY DIFFRACTION8{ D|* }D59 - 249
16X-RAY DIFFRACTION8{ D|* }D300 - 401
17X-RAY DIFFRACTION9{ R|* }R60 - 250
18X-RAY DIFFRACTION9{ R|* }R300 - 401
19X-RAY DIFFRACTION10{ E|* }E59 - 248
20X-RAY DIFFRACTION10{ E|* }E300 - 401
21X-RAY DIFFRACTION11{ S|* }S60 - 250
22X-RAY DIFFRACTION11{ S|* }S300 - 401
23X-RAY DIFFRACTION12{ F|* }F59 - 248
24X-RAY DIFFRACTION12{ F|* }F300 - 401
25X-RAY DIFFRACTION13{ T|* }T64 - 249
26X-RAY DIFFRACTION13{ T|* }T300 - 401
27X-RAY DIFFRACTION14{ G|* }G58 - 250
28X-RAY DIFFRACTION14{ G|* }G300 - 401
29X-RAY DIFFRACTION15{ H|* }H59 - 250
30X-RAY DIFFRACTION15{ H|* }H300 - 401
31X-RAY DIFFRACTION16{ I|* }I58 - 249
32X-RAY DIFFRACTION16{ I|* }I300 - 401
33X-RAY DIFFRACTION17{ J|* }J59 - 248
34X-RAY DIFFRACTION17{ J|* }J300 - 401
35X-RAY DIFFRACTION18{ K|* }K59 - 250
36X-RAY DIFFRACTION18{ K|* }K300 - 401
37X-RAY DIFFRACTION19{ L|* }L58 - 248
38X-RAY DIFFRACTION19{ L|* }L300 - 401
39X-RAY DIFFRACTION20{ M|* }M58 - 248
40X-RAY DIFFRACTION20{ M|* }M300 - 401

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