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- PDB-7acc: human GTP cyclohydrolase I feedback regulatory protein (GFRP) -

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Basic information

Entry
Database: PDB / ID: 7acc
Titlehuman GTP cyclohydrolase I feedback regulatory protein (GFRP)
ComponentsGTP cyclohydrolase 1 feedback regulatory protein
KeywordsPROTEIN BINDING / GTP cyclohydrolase 1 feedback regulatory protein / regulatory protein / L-phenylalanine binding (Phe) synthesis allosteric regulation
Function / homology
Function and homology information


GTP cyclohydrolase binding / negative regulation of biosynthetic process / regulation of nitric oxide biosynthetic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / melanosome / nuclear membrane / dendrite / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
GTP cyclohydrolase I, feedback regulatory protein / GFRP superfamily / GTP cyclohydrolase I feedback regulatory protein (GFRP)
Similarity search - Domain/homology
: / GTP cyclohydrolase 1 feedback regulatory protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 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
DepositionSep 10, 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 31, 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 feedback regulatory protein
B: GTP cyclohydrolase 1 feedback regulatory protein
C: GTP cyclohydrolase 1 feedback regulatory protein
D: GTP cyclohydrolase 1 feedback regulatory protein
E: GTP cyclohydrolase 1 feedback regulatory protein
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)99,74520
Polymers99,35410
Non-polymers39110
Water10,377576
1
A: GTP cyclohydrolase 1 feedback regulatory protein
B: GTP cyclohydrolase 1 feedback regulatory protein
C: GTP cyclohydrolase 1 feedback regulatory protein
D: GTP cyclohydrolase 1 feedback regulatory protein
E: GTP cyclohydrolase 1 feedback regulatory protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,87310
Polymers49,6775
Non-polymers1955
Water905
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11390 Å2
ΔGint-64 kcal/mol
Surface area18210 Å2
MethodPISA
2
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)49,87310
Polymers49,6775
Non-polymers1955
Water905
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11500 Å2
ΔGint-67 kcal/mol
Surface area18200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.27, 107.27, 142.98
Angle α, β, γ (deg.)90, 90, 90
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein
GTP cyclohydrolase 1 feedback regulatory protein / GFRP / GTP cyclohydrolase I feedback regulatory protein / p35


Mass: 9935.432 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCHFR, GFRP / Production host: Escherichia coli (E. coli) / References: UniProt: P30047
#2: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 576 / 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: 2.07 Å3/Da / Density % sol: 40.58 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 2.4 M di-Sodium malonate; pH 7.0 (JCSG F9)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9998 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: 0.9998 Å / Relative weight: 1
ReflectionResolution: 2.04→85.81 Å / Num. obs: 53417 / % possible obs: 99.94 % / Redundancy: 3.6 % / CC1/2: 1 / Net I/σ(I): 26.8
Reflection shellResolution: 2.04→2.12 Å / Num. unique obs: 5243 / CC1/2: 0.7

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1JG5

1jg5


Resolution: 2.04→85.81 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.938 / SU R Cruickshank DPI: 0.19 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.208 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.145
RfactorNum. reflection% reflectionSelection details
Rfree0.1908 2743 -RANDOM
Rwork0.1673 ---
obs0.1685 53417 100 %-
Displacement parametersBiso mean: 33.11 Å2
Baniso -1Baniso -2Baniso -3
1--4.6291 Å20 Å20 Å2
2---4.6291 Å20 Å2
3---9.2583 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: LAST / Resolution: 2.04→85.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6790 0 10 576 7376
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0086969HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.929407HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2495SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1172HARMONIC5
X-RAY DIFFRACTIONt_it6969HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion844SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact6612SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.81
X-RAY DIFFRACTIONt_other_torsion15.71
LS refinement shellResolution: 2.044→2.06 Å
RfactorNum. reflection% reflection
Rfree0.2065 68 -
Rwork0.168 --
obs--100 %
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)
11.86580.440.0491.7930.0341.25420.21230.47630.10160.4763-0.15540.05820.10160.0582-0.05690.151-0.0261-0.128-0.0460.0496-0.064739.2218-37.00215.4422
21.1140.22490.52191.30140.22521.0787-0.00060.10720.12920.10720.13910.18720.12920.1872-0.1385-0.06010.0428-0.05540.0201-0.06440.055749.2489-23.40163.1885
30.88390.0629-0.15421.03380.15040.98660.0573-0.0566-0.1849-0.05660.02220.0967-0.18490.0967-0.07940.0242-0.02980.0099-0.0404-0.03130.032637.8133-5.96861.8598
40.88240.4094-0.25681.4636-0.38520.83560.14130.2154-0.11570.2154-0.1511-0.0963-0.1157-0.09630.00980.069-0.01610.0035-0.0303-0.0474-0.02520.5881-9.22512.8399
50.417-0.1036-0.50490.85870.00672.07450.06730.24160.15070.2416-0.06610.05650.15070.0565-0.00120.1038-0.060.00510.0042-0.0146-0.0921.0699-28.155921.8136
60.85320.2829-0.19020.564-0.01691.66120.0323-0.1572-0.0569-0.15720.0258-0.0413-0.0569-0.0413-0.0580.08030.02850.0067-0.04130.0112-0.040627.4204-18.6844-21.4725
70.60740.38970.08691.8840.43921.5878-0.0293-0.28370.1413-0.28370.14780.09730.14130.0973-0.11860.0827-0.00070.0363-0.0543-0.0301-0.022236.3948-37.5369-18.0266
80.50670.1761-0.14931.61350.74731.3625-0.01120.08370.3320.0837-0.0592-0.05980.332-0.05980.07040.1269-0.0175-0.0125-0.0846-0.015-0.033123.8215-48.3289-5.3643
90.7407-0.0566-0.1712.0505-0.03681.3378-0.01050.06440.17030.0644-0.0723-0.26780.1703-0.26780.08290.0025-0.08480.00620.0133-0.04280.01287.2722-36.693-1.3947
100.9140.0274-0.2271.97190.35531.42850.0264-0.1696-0.1357-0.1696-0.1433-0.3201-0.1357-0.32010.1169-0.02860.0541-0.05030.0662-0.0387-0.01689.1627-18.3643-11.2065
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 84
2X-RAY DIFFRACTION1{ A|* }A85
3X-RAY DIFFRACTION1{ A|* }A86 - 124
4X-RAY DIFFRACTION2{ B|* }B2 - 84
5X-RAY DIFFRACTION2{ B|* }B85
6X-RAY DIFFRACTION2{ B|* }B86 - 135
7X-RAY DIFFRACTION3{ C|* }C-1 - 84
8X-RAY DIFFRACTION3{ C|* }C85
9X-RAY DIFFRACTION3{ C|* }C86 - 150
10X-RAY DIFFRACTION4{ D|* }D2 - 84
11X-RAY DIFFRACTION4{ D|* }D85
12X-RAY DIFFRACTION4{ D|* }D86 - 141
13X-RAY DIFFRACTION5{ E|* }E-1 - 84
14X-RAY DIFFRACTION5{ E|* }E85
15X-RAY DIFFRACTION5{ E|* }E86 - 156
16X-RAY DIFFRACTION6{ F|* }F2 - 84
17X-RAY DIFFRACTION6{ F|* }F85
18X-RAY DIFFRACTION6{ F|* }F86 - 150
19X-RAY DIFFRACTION7{ G|* }G-1 - 84
20X-RAY DIFFRACTION7{ G|* }G85
21X-RAY DIFFRACTION7{ G|* }G86 - 139
22X-RAY DIFFRACTION8{ H|* }H0 - 84
23X-RAY DIFFRACTION8{ H|* }H85
24X-RAY DIFFRACTION8{ H|* }H86 - 155
25X-RAY DIFFRACTION9{ I|* }I2 - 84
26X-RAY DIFFRACTION9{ I|* }I85
27X-RAY DIFFRACTION9{ I|* }I86 - 136
28X-RAY DIFFRACTION10{ J|* }J2 - 84
29X-RAY DIFFRACTION10{ J|* }J85
30X-RAY DIFFRACTION10{ J|* }J86 - 140

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