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- PDB-6w4c: Crystal structure of HAO1 in complex with indazole acid inhibitor... -

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Basic information

Entry
Database: PDB / ID: 6w4c
TitleCrystal structure of HAO1 in complex with indazole acid inhibitor - compound 5
ComponentsHydroxyacid oxidase 1
KeywordsOXIDOREDUCTASE / Inhibitor / Complex
Function / homology
Function and homology information


glyoxylate oxidase / glyoxylate oxidase activity / glycolate catabolic process / (S)-2-hydroxy-acid oxidase / (S)-2-hydroxy-acid oxidase activity / fatty acid alpha-oxidation / Glyoxylate metabolism and glycine degradation / glycine biosynthetic process / peroxisomal matrix / Peroxisomal protein import ...glyoxylate oxidase / glyoxylate oxidase activity / glycolate catabolic process / (S)-2-hydroxy-acid oxidase / (S)-2-hydroxy-acid oxidase activity / fatty acid alpha-oxidation / Glyoxylate metabolism and glycine degradation / glycine biosynthetic process / peroxisomal matrix / Peroxisomal protein import / FMN binding / response to oxidative stress / intracellular membrane-bounded organelle / cytosol
Similarity search - Function
Alpha-hydroxy acid dehydrogenase, FMN-dependent / FMN-dependent alpha-hydroxy acid dehydrogenase, active site / FMN hydroxy acid dehydrogenase domain / FMN-dependent alpha-hydroxy acid dehydrogenases active site. / FMN-dependent alpha-hydroxy acid dehydrogenase domain profile. / FMN-dependent dehydrogenase / FMN-dependent dehydrogenase / Aldolase-type TIM barrel
Similarity search - Domain/homology
FLAVIN MONONUCLEOTIDE / Chem-SL7 / 2-Hydroxyacid oxidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsFerguson, A.D.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Novel, Potent Inhibitors of Hydroxy Acid Oxidase 1 (HAO1) Using DNA-Encoded Chemical Library Screening.
Authors: Lee, E.C.Y. / McRiner, A.J. / Georgiadis, K.E. / Liu, J. / Wang, Z. / Ferguson, A.D. / Levin, B. / von Rechenberg, M. / Hupp, C.D. / Monteiro, M.I. / Keefe, A.D. / Olszewski, A. / Eyermann, ...Authors: Lee, E.C.Y. / McRiner, A.J. / Georgiadis, K.E. / Liu, J. / Wang, Z. / Ferguson, A.D. / Levin, B. / von Rechenberg, M. / Hupp, C.D. / Monteiro, M.I. / Keefe, A.D. / Olszewski, A. / Eyermann, C.J. / Centrella, P. / Liu, Y. / Arora, S. / Cuozzo, J.W. / Zhang, Y. / Clark, M.A. / Huguet, C. / Kohlmann, A.
History
DepositionMar 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1May 19, 2021Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 9, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: 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: Hydroxyacid oxidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5853
Polymers40,7341
Non-polymers8512
Water3,657203
1
A: Hydroxyacid oxidase 1
hetero molecules

A: Hydroxyacid oxidase 1
hetero molecules

A: Hydroxyacid oxidase 1
hetero molecules

A: Hydroxyacid oxidase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,33912
Polymers162,9364
Non-polymers3,4038
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
crystal symmetry operation3_555-y,x,z1
crystal symmetry operation4_555y,-x,z1
Buried area14570 Å2
ΔGint-71 kcal/mol
Surface area44910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)97.079, 97.079, 80.626
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number79
Space group name H-MI4

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Components

#1: Protein Hydroxyacid oxidase 1 / HAOX1 / Glycolate oxidase / GOX


Mass: 40733.918 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HAO1, GOX1, HAOX1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UJM8, (S)-2-hydroxy-acid oxidase
#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-SL7 / 5-[[3-[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]-2-oxidanyl-phenyl]methylamino]-2~{H}-indazole-3-carboxylic acid


Mass: 394.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18N6O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 203 / 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: 2.37 Å3/Da / Density % sol: 48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M TRIS HCl pH 8.5, 25 %(v/v) PEG 550 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Mar 18, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.75→38.25 Å / Num. obs: 37879 / % possible obs: 99.9 % / Redundancy: 7.2 % / Rmerge(I) obs: 0.077 / Net I/σ(I): 25.39
Reflection shellResolution: 1.75→1.78 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 8.84 / Num. unique obs: 1903 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
PHASERphasing
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6W44

6w44


Resolution: 1.75→38.25 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.947 / SU B: 1.752 / SU ML: 0.058 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.1 / ESU R Free: 0.098 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1934 1890 5 %RANDOM
Rwork0.1613 ---
obs0.1628 35989 99.85 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 95.49 Å2 / Biso mean: 19.677 Å2 / Biso min: 8.35 Å2
Baniso -1Baniso -2Baniso -3
1--0.74 Å20 Å20 Å2
2---0.74 Å20 Å2
3---1.48 Å2
Refinement stepCycle: final / Resolution: 1.75→38.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2620 0 60 203 2883
Biso mean--18.87 27.98 -
Num. residues----337
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132783
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172689
X-RAY DIFFRACTIONr_angle_refined_deg1.371.6533776
X-RAY DIFFRACTIONr_angle_other_deg1.3291.5976200
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1465346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.6920.922141
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.9915494
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.951525
X-RAY DIFFRACTIONr_chiral_restr0.0610.2354
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.023223
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02594
LS refinement shellResolution: 1.75→1.793 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.212 147 -
Rwork0.183 2626 -
obs--98.82 %

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