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- PDB-7ala: human GCH-GFRP inhibitory complex -

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Basic information

Entry
Database: PDB / ID: 7ala
Titlehuman GCH-GFRP inhibitory complex
Components(GTP cyclohydrolase ...) x 2
KeywordsHYDROLASE / GTP cyclohydrolase 1 / GTPCH1 / GTP cyclohydrolase I regulatory protein / GFRP / allosteric regulation / complex / allosteric inhibitor
Function / homology
Function and homology information


GTP cyclohydrolase binding / pteridine-containing compound biosynthetic process / dihydrobiopterin metabolic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / neuromuscular process controlling posture / negative regulation of biosynthetic process / GTP-dependent protein binding / regulation of removal of superoxide radicals ...GTP cyclohydrolase binding / pteridine-containing compound biosynthetic process / dihydrobiopterin metabolic process / regulation of lung blood pressure / GTP cyclohydrolase I / GTP cyclohydrolase I activity / neuromuscular process controlling posture / negative regulation of biosynthetic process / GTP-dependent protein binding / regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / neuron projection terminus / regulation of nitric oxide biosynthetic process / 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 / melanosome / cytoplasmic vesicle / protein-containing complex assembly / nuclear membrane / response to lipopolysaccharide / GTPase activity / calcium ion binding / dendrite / 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, feedback regulatory protein / GFRP superfamily / GTP cyclohydrolase I feedback regulatory protein (GFRP) / 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
Chem-5RW / GTP cyclohydrolase 1 feedback regulatory protein / GTP cyclohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.846 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
DepositionOct 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 26, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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 feedback regulatory protein
G: GTP cyclohydrolase 1 feedback regulatory protein
H: GTP cyclohydrolase 1 feedback regulatory protein
I: GTP cyclohydrolase 1 feedback regulatory protein
J: GTP cyclohydrolase 1 feedback regulatory protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,23125
Polymers167,33210
Non-polymers1,89915
Water13,854769
1
A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
E: GTP cyclohydrolase 1
F: GTP cyclohydrolase 1 feedback regulatory protein
G: GTP cyclohydrolase 1 feedback regulatory protein
H: GTP cyclohydrolase 1 feedback regulatory protein
I: GTP cyclohydrolase 1 feedback regulatory protein
J: GTP cyclohydrolase 1 feedback regulatory protein
hetero molecules

A: GTP cyclohydrolase 1
B: GTP cyclohydrolase 1
C: GTP cyclohydrolase 1
D: GTP cyclohydrolase 1
E: GTP cyclohydrolase 1
F: GTP cyclohydrolase 1 feedback regulatory protein
G: GTP cyclohydrolase 1 feedback regulatory protein
H: GTP cyclohydrolase 1 feedback regulatory protein
I: GTP cyclohydrolase 1 feedback regulatory protein
J: GTP cyclohydrolase 1 feedback regulatory protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)338,46250
Polymers334,66520
Non-polymers3,79730
Water36020
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_658-x+1,y,-z+31
Buried area74620 Å2
ΔGint-864 kcal/mol
Surface area89110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.745, 114.013, 113.83
Angle α, β, γ (deg.)90, 130.34, 90
Int Tables number5
Space group name H-MC121

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Components

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GTP cyclohydrolase ... , 2 types, 10 molecules ABCDEFGHIJ

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


Mass: 23473.984 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 (E. coli) / References: UniProt: P30793, GTP cyclohydrolase I
#2: Protein
GTP cyclohydrolase 1 feedback regulatory protein / GFRP / GTP cyclohydrolase I feedback regulatory protein / p35


Mass: 9992.483 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Details: SHMPYLLISTQIRMEVGPTMVGDEQSDPELMQHLGASKRRALGNNFYEYYVDDPPRIVLDKLERRGFRVLSMTGVGQTLV WCLHKE
Source: (gene. exp.) Homo sapiens (human) / Gene: GCHFR, GFRP / Production host: Homo sapiens (human) / References: UniProt: P30047

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Non-polymers , 4 types, 784 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-5RW / 2-azanyl-8-[(4-fluorophenyl)methylsulfanyl]-1,7-dihydropurin-6-one


Mass: 291.304 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C12H10FN5OS / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Na / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 769 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.41 Å3/Da / Density % sol: 48.88 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop
Details: GOL-P4K; 0.1 M MB3 pH 8.5; 0.12 M Monosaccharides (Morpheus F11)

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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: 1.846→81.054 Å / Num. obs: 67925 / % possible obs: 94.5 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.069 / Rsym value: 0.069 / Net I/σ(I): 11.3
Reflection shellResolution: 1.846→2.051 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.634 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3398 / Rsym value: 0.634 / % possible all: 81.1

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
XDSJan 26, 201data reduction
autoPROC1.1.7data scaling
Aimlessdata scaling
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1WPL

1wpl


Resolution: 1.846→39.74 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.913 / SU R Cruickshank DPI: 0.307 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.316 / SU Rfree Blow DPI: 0.208 / SU Rfree Cruickshank DPI: 0.209
RfactorNum. reflection% reflectionSelection details
Rfree0.22 2766 -RANDOM
Rwork0.1853 ---
obs0.1867 67912 50.1 %-
Displacement parametersBiso mean: 36.49 Å2
Baniso -1Baniso -2Baniso -3
1-8.7116 Å20 Å23.0388 Å2
2---3.7643 Å20 Å2
3----4.9473 Å2
Refine analyzeLuzzati coordinate error obs: 0.26 Å
Refinement stepCycle: LAST / Resolution: 1.846→39.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10497 0 110 769 11376
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00810840HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0214648HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3869SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1804HARMONIC5
X-RAY DIFFRACTIONt_it10830HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1386SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact9293SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.71
X-RAY DIFFRACTIONt_other_torsion16.79
LS refinement shellResolution: 1.85→1.97 Å
RfactorNum. reflection% reflection
Rfree0.2295 54 -
Rwork0.2249 --
obs0.2251 1359 5.74 %
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)
11.0048-0.14751.54990.1084-0.40582.42840.2061-0.0480.7488-0.048-0.16920.09690.74880.0969-0.03690.39870.10360.1058-0.18890.0174-0.1969-20.776-35.7284119.5814
21.21451.26771.80851.26861.68423.59730.0543-0.08250.3019-0.08250.04670.41110.30190.4111-0.101-0.05280.13940.07540.16540.0622-0.1496-1.7977-8.1724122.2619
30.768-0.7201-1.19151.96621.43552.56020.0602-0.0382-0.2068-0.03820.11390.29-0.20680.29-0.17410.1058-0.05870.0177-0.0508-0.0221-0.127-18.655416.6663119.9968
42.17060.4127-1.09580.35990.15772.30770.09580.0332-0.2970.0332-0.0818-0.2973-0.297-0.2973-0.0140.0870.07390.0583-0.0544-0.0125-0.0744-48.59637.9194116.0128
50.39791.2421-0.54632.2605-1.39232.31880.11780.10460.22420.1046-0.0753-0.25180.2242-0.2518-0.04250.1571-0.10950.1303-0.0831-0.0519-0.1207-49.6084-25.5859116.6175
61.19650.0813-0.84092.96890.50312.9877-0.0018-0.2385-0.1725-0.2385-0.0327-0.2691-0.1725-0.26910.03450.05110.0262-0.0333-0.0664-0.0092-0.1053-38.5941-0.423579.095
71.68250.1270.12541.30560.26082.29140.0046-0.1739-0.284-0.1739-0.09110.1945-0.2840.19450.08660.17130.00240.034-0.12910.0325-0.1193-20.14858.367181.8419
82.4594-0.14390.18291.3362-0.28122.2099-0.0053-0.2073-0.0344-0.2073-0.08420.4321-0.03440.43210.0895-0.02410.00120.05630.06550.0469-0.117-5.6157-6.386883.6511
91.38590.92770.45222.10040.35892.79-0.0678-0.11650.4526-0.1165-00.39220.45260.39220.06780.12020.15490.0814-0.07390.0077-0.1127-15.4274-25.346682.296
101.99740.2022-0.60731.98340.16792.6589-0.0618-0.18140.2621-0.1814-0.05-0.22290.2621-0.22290.11180.1672-0.03190.0223-0.1476-0.0376-0.1282-35.8025-21.280879.5365
112.02410.7113-0.90772.89420.5551-0.6693-0.2304-1.15410.1942-1.1541-0.00780.09340.19420.09340.23820.3397-0.0760.0767-0.1495-0.0296-0.2731-26.8997-8.680199.9791
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A58 - 249
2X-RAY DIFFRACTION1{ A|* }A250
3X-RAY DIFFRACTION2{ B|* }B68 - 249
4X-RAY DIFFRACTION2{ B|* }B250
5X-RAY DIFFRACTION3{ C|* }C58 - 249
6X-RAY DIFFRACTION3{ C|* }C250
7X-RAY DIFFRACTION4{ D|* }D57 - 249
8X-RAY DIFFRACTION4{ D|* }D250
9X-RAY DIFFRACTION5{ E|* }E58 - 249
10X-RAY DIFFRACTION5{ E|* }E250
11X-RAY DIFFRACTION6{ F|* }F-2 - 84
12X-RAY DIFFRACTION6{ F|* }F85
13X-RAY DIFFRACTION7{ G|* }G1 - 84
14X-RAY DIFFRACTION7{ G|* }G85
15X-RAY DIFFRACTION8{ H|* }H1 - 84
16X-RAY DIFFRACTION8{ H|* }H85
17X-RAY DIFFRACTION9{ I|* }I-2 - 83
18X-RAY DIFFRACTION9{ I|* }I85
19X-RAY DIFFRACTION10{ J|* }J-1 - 84
20X-RAY DIFFRACTION10{ J|* }J85
21X-RAY DIFFRACTION11{ X|* }X1 - 5

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