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- PDB-7alc: human GCH-GFRP stimulatory complex -

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Basic information

Entry
Database: PDB / ID: 7alc
Titlehuman GCH-GFRP stimulatory complex
Components
  • GTP cyclohydrolase 1
  • GTP cyclohydrolase 1 feedback regulatory protein
KeywordsHYDROLASE / GTP cyclohydrolase 1 / GTPCH1 / GTP cyclohydrolase I regulatory protein / GFRP / allosteric regulation / complex / allosteric regulator
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 / negative regulation of biosynthetic process / neuromuscular process controlling posture / 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 / negative regulation of biosynthetic process / neuromuscular process controlling posture / 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 / positive regulation of heart rate / response to pain / 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 / dendrite / 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, 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
PHENYLALANINE / GTP cyclohydrolase 1 feedback regulatory protein / GTP cyclohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.726 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)168,48520
Polymers167,33210
Non-polymers1,15310
Water17,637979
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)336,97140
Polymers334,66520
Non-polymers2,30620
Water36020
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_556-x,y,-z+11
Buried area64340 Å2
ΔGint-741 kcal/mol
Surface area94060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.853, 113.922, 113.910
Angle α, β, γ (deg.)90.000, 130.210, 90.000
Int Tables number5
Space group name H-MC121

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Components

#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: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P30047
#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-PHE / PHENYLALANINE


Type: L-peptide linking / Mass: 165.189 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C9H11NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 979 / 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: 2.44 Å3/Da / Density % sol: 49.5 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 6 / Details: 2 M NaCl; 0.1 M NaCit pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.726→86.99 Å / Num. obs: 162888 / % possible obs: 99.1 % / Redundancy: 3.5 % / CC1/2: 0.998 / Net I/σ(I): 7.9
Reflection shellResolution: 1.726→1.934 Å / Num. unique obs: 44799 / CC1/2: 0.26 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (18-SEP-2020)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IS8

1is8


Resolution: 1.726→86.99 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.923 / SU R Cruickshank DPI: 0.172 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.177 / SU Rfree Blow DPI: 0.151 / SU Rfree Cruickshank DPI: 0.15
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2273 3017 2.88 %RANDOM
Rwork0.197 ---
obs0.1979 104792 62.6 %-
Displacement parametersBiso max: 77.57 Å2 / Biso mean: 28.14 Å2 / Biso min: 5.74 Å2
Baniso -1Baniso -2Baniso -3
1-0.7067 Å20 Å20.8551 Å2
2--0.3058 Å20 Å2
3----1.0125 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 1.726→86.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10174 0 65 979 11218
Biso mean--15.81 37.59 -
Num. residues----1282
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3727SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1736HARMONIC5
X-RAY DIFFRACTIONt_it10415HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1347SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9718SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d10470HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg14148HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion3.77
X-RAY DIFFRACTIONt_other_torsion16.48
LS refinement shellResolution: 1.73→1.86 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2727 68 3.24 %
Rwork0.216 2028 -
all0.2178 2096 -
obs--6.38 %
Refinement TLS params.

Method: refined / 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)
10.5404-0.29260.58470-0.32851.03160.0045-0.0180.0001-0.0196-0.005-0.01340.1268-0.04420.00050.04370.00720.0027-0.03150.0021-0.0304-28.7196-22.760732.9098
21.01321.06331.25050.90331.53592.74640.12630.0053-0.05990.0360.0478-0.09690.14420.1425-0.1742-0.03240.0043-0.0126-0.0088-0.0123-0.0231-8.38953.975935.6808
30.3275-0.5538-0.75040.87241.28552.13650.0298-0.02030.01130.01230.058-0.1015-0.07230.1179-0.08780.026-0.00910.0002-0.0151-0.0068-0.0572-27.382928.981233.3229
40.83060.2291-0.33960.0006-0.32090.4340.0273-0.00710.01570.04760.04980.0442-0.1479-0.0253-0.07710.03150.05090.0595-0.01910.0182-0.0189-56.603521.671329.6013
50.20590.5753-0.47911.3105-1.00571.35170.08720.02080.06870.08580.01210.1291-0.0656-0.1067-0.0993-0.0204-0.01280.0341-0.00210.0005-0.0173-57.3777-12.381630.0477
60.96890.35670.00311.1-0.18391.3964-0.03760.0953-0.0506-0.127-0.0059-0.18860.23760.10710.04350.00330.02660.0493-0.003-0.026-0.0389-22.6858-11.4755-3.9713
71.2296-0.2431-0.09840.9434-0.2451.6542-0.02790.10170.0857-0.1085-0.0367-0.0388-0.03040.19560.0646-0.0396-0.02530.02520.02730.0177-0.0476-13.81057.2596-3.0467
80.65090.27690.26381.5569-0.47891.60320.0065-0.0050.0584-0.0588-0.06260.0147-0.06340.13420.0561-0.00060.01150.0084-0.01670.0096-0.054-28.772121.3298-4.5964
90.42920.1215-0.41651.87340.02221.73130.01860.066-0.0304-0.1790.03010.1777-0.1086-0.2246-0.0487-0.01420.0163-0.0270.00210.005-0.0365-46.722311.7571-7.0675
100.8140.24870.11911.32130.87362.0260.01310.0121-0.1032-0.0775-0.0580.0396-0.0396-0.09060.04490.0055-0.00660.0048-0.0413-0.0167-0.0453-43.0572-8.827-6.2119
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A58 - 249
2X-RAY DIFFRACTION2{ B|* }B63 - 249
3X-RAY DIFFRACTION3{ C|* }C68 - 249
4X-RAY DIFFRACTION4{ D|* }D58 - 249
5X-RAY DIFFRACTION5{ E|* }E58 - 249
6X-RAY DIFFRACTION6{ F|* }F1 - 83
7X-RAY DIFFRACTION7{ G|* }G1 - 84
8X-RAY DIFFRACTION8{ H|* }H1 - 83
9X-RAY DIFFRACTION9{ I|* }I-1 - 83
10X-RAY DIFFRACTION10{ J|* }J1 - 82

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