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- PDB-8im2: Crystal structure of human HPPD complexed with NTBC -

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Basic information

Entry
Database: PDB / ID: 8im2
TitleCrystal structure of human HPPD complexed with NTBC
Components4-hydroxyphenylpyruvate dioxygenase
KeywordsOXIDOREDUCTASE / Enzyme / Inhibitor / Complex
Function / homology
Function and homology information


Tyrosine catabolism / 4-hydroxyphenylpyruvate dioxygenase / 4-hydroxyphenylpyruvate dioxygenase activity / L-tyrosine catabolic process / L-phenylalanine catabolic process / Golgi membrane / endoplasmic reticulum membrane / protein homodimerization activity / extracellular exosome / metal ion binding / cytosol
Similarity search - Function
4-hydroxyphenylpyruvate dioxygenase / 4-hydroxyphenylpyruvate dioxygenase, C-terminal / 4-hydroxyphenylpyruvate dioxygenase, N-terminal / Glyoxalase/fosfomycin resistance/dioxygenase domain / Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily / Vicinal oxygen chelate (VOC) domain / Vicinal oxygen chelate (VOC) domain profile. / Glyoxalase/Bleomycin resistance protein/Dihydroxybiphenyl dioxygenase
Similarity search - Domain/homology
: / Chem-NTD / 4-hydroxyphenylpyruvate dioxygenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.81 Å
AuthorsDong, J. / Lin, H.-Y. / Yang, G.-F.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Structure / Year: 2023
Title: Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.
Authors: Dong, J. / Xiao, H. / Chen, J.N. / Zheng, B.F. / Xu, Y.L. / Chen, M.X. / Yang, W.C. / Lin, H.Y. / Yang, G.F.
History
DepositionMar 5, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 4-hydroxyphenylpyruvate dioxygenase
B: 4-hydroxyphenylpyruvate dioxygenase
C: 4-hydroxyphenylpyruvate dioxygenase
D: 4-hydroxyphenylpyruvate dioxygenase
E: 4-hydroxyphenylpyruvate dioxygenase
F: 4-hydroxyphenylpyruvate dioxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)273,01624
Polymers269,9786
Non-polymers3,03818
Water1,49583
1
A: 4-hydroxyphenylpyruvate dioxygenase
E: 4-hydroxyphenylpyruvate dioxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,0058
Polymers89,9932
Non-polymers1,0136
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6300 Å2
ΔGint-65 kcal/mol
Surface area30280 Å2
MethodPISA
2
B: 4-hydroxyphenylpyruvate dioxygenase
F: 4-hydroxyphenylpyruvate dioxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,0058
Polymers89,9932
Non-polymers1,0136
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6410 Å2
ΔGint-62 kcal/mol
Surface area28940 Å2
MethodPISA
3
C: 4-hydroxyphenylpyruvate dioxygenase
D: 4-hydroxyphenylpyruvate dioxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)91,0058
Polymers89,9932
Non-polymers1,0136
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6180 Å2
ΔGint-61 kcal/mol
Surface area29640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.550, 147.442, 133.930
Angle α, β, γ (deg.)90.00, 97.12, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
4-hydroxyphenylpyruvate dioxygenase / 4-hydroxyphenylpyruvic acid oxidase / 4HPPD / HPD / HPPDase


Mass: 44996.250 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HPD, PPD
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P32754, 4-hydroxyphenylpyruvate dioxygenase
#2: Chemical
ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Co
#3: Chemical
ChemComp-NTD / 2-{HYDROXY[2-NITRO-4-(TRIFLUOROMETHYL)PHENYL]METHYLENE}CYCLOHEXANE-1,3-DIONE


Mass: 329.228 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C14H10F3NO5
#4: Chemical
ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.33 Å3/Da / Density % sol: 47.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.03M CaCl2, 0.03M MgCl2, 0.05M Tris, 0.05M Bicine, pH8.5, 25% MPD, 25% PEG 1000, 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9875 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9875 Å / Relative weight: 1
ReflectionResolution: 2.8→30 Å / Num. obs: 55147 / % possible obs: 96.8 % / Redundancy: 5.6 % / CC1/2: 0.988 / Rmerge(I) obs: 0.121 / Net I/σ(I): 17.6
Reflection shellResolution: 2.8→2.85 Å / Rmerge(I) obs: 0.544 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2660 / CC1/2: 0.83

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.81→29.67 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2542 2678 4.86 %
Rwork0.2134 --
obs0.2154 55113 96.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.81→29.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms17464 0 192 83 17739
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00418110
X-RAY DIFFRACTIONf_angle_d0.73924575
X-RAY DIFFRACTIONf_dihedral_angle_d20.2256556
X-RAY DIFFRACTIONf_chiral_restr0.0522661
X-RAY DIFFRACTIONf_plane_restr0.0053171
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.81-2.860.3571160.30372507X-RAY DIFFRACTION88
2.86-2.910.36611180.28962684X-RAY DIFFRACTION93
2.91-2.970.35251560.28342810X-RAY DIFFRACTION99
2.97-3.040.34831390.26922855X-RAY DIFFRACTION100
3.04-3.110.31821620.25952810X-RAY DIFFRACTION99
3.11-3.180.29581520.24592848X-RAY DIFFRACTION99
3.18-3.270.28151650.24752811X-RAY DIFFRACTION99
3.27-3.370.33161480.24292826X-RAY DIFFRACTION99
3.37-3.470.26191470.23012815X-RAY DIFFRACTION99
3.47-3.60.23541300.21042855X-RAY DIFFRACTION99
3.6-3.740.24951370.20882829X-RAY DIFFRACTION99
3.74-3.910.23251560.20762819X-RAY DIFFRACTION99
3.91-4.120.25141550.22761X-RAY DIFFRACTION97
4.12-4.380.24051220.18092639X-RAY DIFFRACTION91
4.38-4.710.18961260.1682834X-RAY DIFFRACTION99
4.71-5.180.23371550.19062818X-RAY DIFFRACTION99
5.18-5.930.23541570.19942851X-RAY DIFFRACTION99
5.93-7.450.24751320.21652802X-RAY DIFFRACTION97
7.45-29.670.19711050.18912261X-RAY DIFFRACTION77
Refinement TLS params.Method: refined / Origin x: 112.651 Å / Origin y: 10.8592 Å / Origin z: 298.3061 Å
111213212223313233
T0.2005 Å20.0514 Å2-0.0263 Å2-0.1526 Å20.0068 Å2--0.2049 Å2
L0.2167 °20.007 °2-0.2793 °2--0.0223 °20.063 °2--0.3281 °2
S0.0862 Å °-0.0087 Å °-0.0827 Å °-0.0105 Å °-0.0701 Å °0.0081 Å °-0.1545 Å °-0.0554 Å °0.0102 Å °
Refinement TLS groupSelection details: all

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