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- PDB-8gsq: Structure based studies reveal an atypical antipsychotic drug can... -

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Basic information

Entry
Database: PDB / ID: 8gsq
TitleStructure based studies reveal an atypical antipsychotic drug candidate - Paliperidone as a potent hSOD1 modulator with implications in ALS treatment.
Components(Superoxide dismutase [Cu- ...) x 4
KeywordsOXIDOREDUCTASE / Superoxide Dismutase / ALS / antipsychotic / oxidation / oxidoreductase-inhibitor complex
Function / homology
Function and homology information


response to antipsychotic drug / response to carbon monoxide / dense core granule / : / action potential initiation / cellular response to potassium ion / neurofilament cytoskeleton organization / anterograde axonal transport / retrograde axonal transport / positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway ...response to antipsychotic drug / response to carbon monoxide / dense core granule / : / action potential initiation / cellular response to potassium ion / neurofilament cytoskeleton organization / anterograde axonal transport / retrograde axonal transport / positive regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / protein phosphatase 2B binding / regulation of organ growth / relaxation of vascular associated smooth muscle / response to superoxide / peripheral nervous system myelin maintenance / regulation of T cell differentiation in thymus / superoxide anion generation / retina homeostasis / negative regulation of cholesterol biosynthetic process / hydrogen peroxide biosynthetic process / auditory receptor cell stereocilium organization / regulation of protein kinase activity / response to copper ion / myeloid cell homeostasis / cellular response to ATP / muscle cell cellular homeostasis / regulation of GTPase activity / heart contraction / superoxide metabolic process / positive regulation of catalytic activity / superoxide dismutase / Detoxification of Reactive Oxygen Species / transmission of nerve impulse / negative regulation of reproductive process / negative regulation of developmental process / superoxide dismutase activity / neuronal action potential / regulation of multicellular organism growth / response to axon injury / ectopic germ cell programmed cell death / glutathione metabolic process / positive regulation of phagocytosis / ovarian follicle development / axon cytoplasm / embryo implantation / cellular response to cadmium ion / response to amphetamine / reactive oxygen species metabolic process / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / dendrite cytoplasm / removal of superoxide radicals / response to nutrient levels / positive regulation of superoxide anion generation / regulation of mitochondrial membrane potential / thymus development / locomotory behavior / placenta development / response to organic substance / positive regulation of cytokine production / determination of adult lifespan / sensory perception of sound / response to hydrogen peroxide / mitochondrial intermembrane space / small GTPase binding / regulation of blood pressure / negative regulation of inflammatory response / peroxisome / Platelet degranulation / gene expression / response to heat / protein-folding chaperone binding / cytoplasmic vesicle / spermatogenesis / response to ethanol / intracellular iron ion homeostasis / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / lysosome / mitochondrial matrix / response to xenobiotic stimulus / positive regulation of apoptotic process / copper ion binding / response to antibiotic / neuronal cell body / apoptotic process / protein-containing complex / mitochondrion / extracellular space / extracellular exosome / zinc ion binding / extracellular region / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Copper/Zinc superoxide dismutase signature 1. / Superoxide dismutase, copper/zinc, binding site / Copper/Zinc superoxide dismutase signature 2. / Superoxide dismutase, copper/zinc binding domain / Superoxide dismutase (Cu/Zn) / superoxide dismutase copper chaperone / Copper/zinc superoxide dismutase (SODC) / Superoxide dismutase-like, copper/zinc binding domain superfamily
Similarity search - Domain/homology
Chem-K4I / Superoxide dismutase [Cu-Zn] / Superoxide dismutase [Cu-Zn]
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsAouti, S. / Padmanabhan, B.
Funding support India, 1items
OrganizationGrant numberCountry
Indian Council of Medical Research India
CitationJournal: Acta Crystallogr D Struct Biol / Year: 2023
Title: Structure-based discovery of an antipsychotic drug, paliperidone, as a modulator of human superoxide dismutase 1: a potential therapeutic target in amyotrophic lateral sclerosis.
Authors: Aouti, S. / Padavattan, S. / Padmanabhan, B.
History
DepositionSep 6, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Item: _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_assembly_prop.value

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Superoxide dismutase [Cu-Zn]
B: Superoxide dismutase [Cu-Zn]
C: Superoxide dismutase [Cu-Zn]
D: Superoxide dismutase [Cu-Zn]
E: Superoxide dismutase [Cu-Zn]
F: Superoxide dismutase [Cu-Zn]
G: Superoxide dismutase [Cu-Zn]
H: Superoxide dismutase [Cu-Zn]
I: Superoxide dismutase [Cu-Zn]
J: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,80226
Polymers159,23410
Non-polymers1,56816
Water17,853991
1
A: Superoxide dismutase [Cu-Zn]
B: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2336
Polymers31,9182
Non-polymers3154
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-12 kcal/mol
Surface area13890 Å2
MethodPISA
2
C: Superoxide dismutase [Cu-Zn]
D: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3046
Polymers31,9892
Non-polymers3154
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1420 Å2
ΔGint-12 kcal/mol
Surface area13890 Å2
MethodPISA
3
E: Superoxide dismutase [Cu-Zn]
F: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1146
Polymers31,7992
Non-polymers3154
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-11 kcal/mol
Surface area13890 Å2
MethodPISA
4
G: Superoxide dismutase [Cu-Zn]
H: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1034
Polymers31,6112
Non-polymers4922
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1350 Å2
ΔGint-11 kcal/mol
Surface area13460 Å2
MethodPISA
5
I: Superoxide dismutase [Cu-Zn]
J: Superoxide dismutase [Cu-Zn]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0484
Polymers31,9182
Non-polymers1312
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1360 Å2
ΔGint-12 kcal/mol
Surface area13840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)163.793, 202.455, 143.996
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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Superoxide dismutase [Cu- ... , 4 types, 10 molecules ABDFIJCEGH

#1: Protein
Superoxide dismutase [Cu-Zn] / Superoxide dismutase 1 / hSod1


Mass: 15958.757 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOD1 / Plasmid: pETM11 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P00441, superoxide dismutase
#2: Protein Superoxide dismutase [Cu-Zn] / Superoxide dismutase 1 / hSod1


Mass: 16029.835 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SOD1 / Plasmid: pETM11 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P00441, superoxide dismutase
#3: Protein Superoxide dismutase [Cu-Zn] / Superoxide dismutase 1 / hSod1


Mass: 15840.603 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HEL-S-44 / Plasmid: pETM11 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: V9HWC9, superoxide dismutase
#4: Protein Superoxide dismutase [Cu-Zn]


Mass: 15770.510 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HEL-S-44 / Plasmid: pETM11 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: V9HWC9, superoxide dismutase

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Non-polymers , 4 types, 1007 molecules

#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-K4I / (9~{R})-3-[2-[4-(6-fluoranyl-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-9-oxidanyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one


Mass: 426.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27FN4O3 / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 991 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.78 Å3/Da / Density % sol: 67.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: Sodium Citrate

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Data collection

DiffractionMean temperature: 293 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.9655 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Feb 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9655 Å / Relative weight: 1
ReflectionResolution: 2.04→101.23 Å / Num. obs: 142935 / % possible obs: 94.5 % / Redundancy: 6.6 % / Biso Wilson estimate: 33.81 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.04 / Rrim(I) all: 0.103 / Net I/σ(I): 12.9
Reflection shellResolution: 2.04→2.076 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.911 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 7478 / CC1/2: 0.769 / Rpim(I) all: 0.393 / Rrim(I) all: 0.994 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
autoPROCv1.1.7data reduction
autoPROCv1.1.7data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6a9o

6a9o


Resolution: 2.1→95.39 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2078 6508 4.99 %
Rwork0.1744 --
obs0.176 130482 94.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→95.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10963 0 76 991 12030
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d0.857
X-RAY DIFFRACTIONf_dihedral_angle_d7.3631611
X-RAY DIFFRACTIONf_chiral_restr0.0591679
X-RAY DIFFRACTIONf_plane_restr0.0052072
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.120.24172380.21754310X-RAY DIFFRACTION100
2.12-2.150.26612120.21284389X-RAY DIFFRACTION100
2.15-2.180.24772370.21894356X-RAY DIFFRACTION100
2.18-2.20.26232500.21854353X-RAY DIFFRACTION100
2.2-2.230.29252020.22484020X-RAY DIFFRACTION93
2.23-2.2300.279916X-RAY DIFFRACTION5
2.26-2.290.25192200.21414044X-RAY DIFFRACTION99
2.29-2.330.22322050.21054372X-RAY DIFFRACTION100
2.33-2.370.26172280.21724399X-RAY DIFFRACTION100
2.37-2.40.26442030.22194395X-RAY DIFFRACTION100
2.4-2.450.25722420.22854318X-RAY DIFFRACTION100
2.45-2.490.292310.2264396X-RAY DIFFRACTION100
2.49-2.540.2862170.21514378X-RAY DIFFRACTION100
2.54-2.590.26772310.21134392X-RAY DIFFRACTION100
2.59-2.650.27862270.21834233X-RAY DIFFRACTION98
2.65-2.710.2419920.22941650X-RAY DIFFRACTION38
2.71-2.780.2532430.22264387X-RAY DIFFRACTION100
2.78-2.850.25882480.22694335X-RAY DIFFRACTION100
2.85-2.930.24462560.23324369X-RAY DIFFRACTION100
2.93-3.030.25492320.20874406X-RAY DIFFRACTION100
3.03-3.140.20352290.18384371X-RAY DIFFRACTION100
3.14-3.260.21022230.17034421X-RAY DIFFRACTION100
3.26-3.410.19992540.16524384X-RAY DIFFRACTION100
3.41-3.590.18582320.16284407X-RAY DIFFRACTION100
3.59-3.820.17972130.1554438X-RAY DIFFRACTION100
3.82-4.110.15862320.13174405X-RAY DIFFRACTION100
4.11-4.520.15422150.12154459X-RAY DIFFRACTION100
4.52-5.180.14992330.12754455X-RAY DIFFRACTION100
5.18-6.520.17562310.1524494X-RAY DIFFRACTION100
6.52-95.390.19492320.16114622X-RAY DIFFRACTION99

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