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- PDB-4xwy: Crystal structure of human sepiapterin reductase in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4xwy
TitleCrystal structure of human sepiapterin reductase in complex with an N-acetylserotinin analogue
ComponentsSepiapterin reductase
KeywordsOXIDOREDUCTASE / inhibitor / complex
Function / homology
Function and homology information


sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming) / sepiapterin reductase activity / aldo-keto reductase (NADPH) activity / tetrahydrobiopterin biosynthetic process / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / nitric oxide biosynthetic process / NADP binding / extracellular exosome / nucleoplasm / cytosol
Similarity search - Function
Sepiapterin reductase / short chain dehydrogenase / Short-chain dehydrogenase/reductase SDR / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-43O / Chem-NDP / Sepiapterin reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.35 Å
AuthorsJohnsson, K. / Hovius, R. / Gorszka, K.I. / Pojer, F.
CitationJournal: Neuron / Year: 2015
Title: Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway.
Authors: Latremoliere, A. / Latini, A. / Andrews, N. / Cronin, S.J. / Fujita, M. / Gorska, K. / Hovius, R. / Romero, C. / Chuaiphichai, S. / Painter, M. / Miracca, G. / Babaniyi, O. / Remor, A.P. / ...Authors: Latremoliere, A. / Latini, A. / Andrews, N. / Cronin, S.J. / Fujita, M. / Gorska, K. / Hovius, R. / Romero, C. / Chuaiphichai, S. / Painter, M. / Miracca, G. / Babaniyi, O. / Remor, A.P. / Duong, K. / Riva, P. / Barrett, L.B. / Ferreiros, N. / Naylor, A. / Penninger, J.M. / Tegeder, I. / Zhong, J. / Blagg, J. / Channon, K.M. / Johnsson, K. / Costigan, M. / Woolf, C.J.
History
DepositionJan 29, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Nov 25, 2015Group: Data collection
Revision 1.2Jan 10, 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

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Assembly

Deposited unit
A: Sepiapterin reductase
B: Sepiapterin reductase
C: Sepiapterin reductase
D: Sepiapterin reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,46121
Polymers119,5664
Non-polymers4,89517
Water4,486249
1
A: Sepiapterin reductase
C: Sepiapterin reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,27911
Polymers59,7832
Non-polymers2,4969
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6970 Å2
ΔGint-84 kcal/mol
Surface area19920 Å2
MethodPISA
2
B: Sepiapterin reductase
D: Sepiapterin reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,18310
Polymers59,7832
Non-polymers2,4008
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7090 Å2
ΔGint-86 kcal/mol
Surface area20190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)144.840, 144.840, 180.695
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61

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Components

#1: Protein
Sepiapterin reductase / / SPR


Mass: 29891.414 Da / Num. of mol.: 4 / Fragment: residues 15-275
Source method: isolated from a genetically manipulated source
Details: The N-termius" MHHHHHHENLYFQG" was added for purification M15 is original start codon of the protein residues 1-17 "MHHHHHHENLYFQGMEG" and 275 "K" are not resolved in the structure
Source: (gene. exp.) Homo sapiens (human) / Gene: SPR / Plasmid: pET9a / Production host: Escherichia coli bl21(de3) (bacteria)
References: UniProt: P35270, sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming)
#2: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical
ChemComp-43O / N-[2-(5-hydroxy-2-methyl-1H-indol-3-yl)ethyl]-2-methoxyacetamide


Mass: 262.304 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H18N2O3
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 249 / Source method: isolated from a natural source / Formula: H2O

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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: 4.58 Å3/Da / Density % sol: 73.12 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 2% W/V PEG1000, 2.5% V/V glycerol, 1.7 M Ammonium sulfate, 0.1 M Hepes
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99999 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 11, 2014
RadiationMonochromator: SI(111) MONOCHROMATOR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.35→125.435 Å / Num. all: 89220 / Num. obs: 89220 / % possible obs: 100 % / Redundancy: 11.2 % / Biso Wilson estimate: 55.8 Å2 / Rpim(I) all: 0.03 / Rrim(I) all: 0.1 / Rsym value: 0.096 / Net I/av σ(I): 6.536 / Net I/σ(I): 15.8 / Num. measured all: 998773
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.35-2.4811.50.7161149858130180.220.7163.4100
2.48-2.6311.30.4361.7139323123120.1350.4365.1100
2.63-2.8110.70.312.4123302115190.0990.316.6100
2.81-3.0310.60.1973.7114318107780.0630.1979.6100
3.03-3.3211.70.1245.711604699050.0380.12415.7100
3.32-3.7211.30.0947.210187589940.0290.09422.7100
3.72-4.2910.40.0778.48215179080.0250.07728.3100
4.29-5.25120.05412.28053867090.0160.05436.9100
5.25-7.4311.50.05112.45953051980.0160.05131.8100
7.43-46.30811.10.03515.83183228790.0110.03544.999.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.555
Highest resolutionLowest resolution
Rotation46.31 Å2.77 Å

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Processing

Software
NameVersionClassification
PDB_EXTRACT3.15data extraction
REFMAC5.8.0103refinement
Coot0.8.1model building
MOLREP11.2.08phasing
SCALA3.3.21data scaling
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HWK

4hwk


Resolution: 2.35→125.435 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.937 / WRfactor Rfree: 0.1983 / WRfactor Rwork: 0.1699 / FOM work R set: 0.8433 / SU B: 5.423 / SU ML: 0.126 / SU R Cruickshank DPI: 0.1789 / SU Rfree: 0.1629 / Cross valid method: FREE R-VALUE / σ(F): 0 / ESU R: 0.179 / ESU R Free: 0.163 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2167 4682 5.3 %RANDOM
Rwork0.1852 84419 --
obs0.1868 84419 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 200.07 Å2 / Biso mean: 48.374 Å2 / Biso min: 21.32 Å2
Baniso -1Baniso -2Baniso -3
1-0.67 Å20.33 Å20 Å2
2--0.67 Å20 Å2
3----2.17 Å2
Refine analyzeLuzzati coordinate error obs: 0.296 Å
Refinement stepCycle: final / Resolution: 2.35→125.435 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7744 0 313 249 8306
Biso mean--42.78 44.16 -
Num. residues----1028
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0198208
X-RAY DIFFRACTIONr_bond_other_d0.0010.028048
X-RAY DIFFRACTIONr_angle_refined_deg1.2192.0511162
X-RAY DIFFRACTIONr_angle_other_deg0.6583.00318504
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.41451040
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.224.103312
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.712151404
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.3071564
X-RAY DIFFRACTIONr_chiral_restr0.0650.21297
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0219132
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021752
X-RAY DIFFRACTIONr_mcbond_it4.6644.5054124
X-RAY DIFFRACTIONr_mcbond_other4.6624.5054123
X-RAY DIFFRACTIONr_mcangle_it6.4496.7495152
LS refinement shellResolution: 2.35→2.411 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.321 318 -
Rwork0.277 6284 -
all-6602 -
obs--99.92 %

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