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- PDB-8d3h: Crystal structure of human Apoptosis-Inducing Factor (AIF) W196A ... -

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Basic information

Entry
Database: PDB / ID: 8d3h
TitleCrystal structure of human Apoptosis-Inducing Factor (AIF) W196A mutant complexed with 7-chloroquinolin-4-amine
Components(Apoptosis-inducing factor 1, ...) x 2
KeywordsOXIDOREDUCTASE / mitochondrial import / oxidative phosphorylation / SAXS
Function / homology
Function and homology information


Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / regulation of apoptotic DNA fragmentation / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / poly-ADP-D-ribose binding / NAD(P)H oxidase H2O2-forming activity / cellular response to aldosterone / positive regulation of necroptotic process / NADH dehydrogenase activity / oxidoreductase activity, acting on NAD(P)H ...Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors / regulation of apoptotic DNA fragmentation / mitochondrial respiratory chain complex assembly / protein import into mitochondrial intermembrane space / poly-ADP-D-ribose binding / NAD(P)H oxidase H2O2-forming activity / cellular response to aldosterone / positive regulation of necroptotic process / NADH dehydrogenase activity / oxidoreductase activity, acting on NAD(P)H / chromosome condensation / response to L-glutamate / mitochondrial respiratory chain complex I assembly / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / cellular response to nitric oxide / FAD binding / cellular response to estradiol stimulus / response to ischemia / mitochondrial intermembrane space / neuron differentiation / response to toxic substance / cellular response to hydrogen peroxide / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron apoptotic process / cellular response to hypoxia / neuron apoptotic process / mitochondrial inner membrane / protein dimerization activity / positive regulation of apoptotic process / apoptotic process / perinuclear region of cytoplasm / mitochondrion / DNA binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Mitochondrial apoptosis-inducing factor, C-terminal domain / Apoptosis-inducing factor, mitochondrion-associated, C-term / Apoptosis-inducing factor, mitochondrion-associated, C-term / FAD/NAD-linked reductase, dimerisation domain superfamily / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / FAD/NAD(P)-binding domain superfamily
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / 7-chloroquinolin-4-amine / Apoptosis-inducing factor 1, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsBrosey, C.A. / Tainer, J.A.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA220430 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P01 CA092584 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP180813 United States
CitationJournal: To Be Published
Title: Integrating early structural selection into chemical library screening for drug discovery with high-throughput small-angle X-ray scattering (SAXS)
Authors: Brosey, C.A. / Link, T. / Shen, R. / Moiani, D. / Burnett, K. / Hura, G. / Jones, D.E. / Tainer, J.A.
History
DepositionJun 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 8, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Apoptosis-inducing factor 1, mitochondrial
B: Apoptosis-inducing factor 1, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,7497
Polymers118,7592
Non-polymers1,9905
Water3,243180
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS, AIF-W196A exists as a monomer-dimer equilibrium in solution.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)90.787, 114.767, 120.907
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Apoptosis-inducing factor 1, ... , 2 types, 2 molecules AB

#1: Protein Apoptosis-inducing factor 1, mitochondrial / / Programmed cell death protein 8


Mass: 59371.434 Da / Num. of mol.: 1 / Mutation: W196A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIFM1, AIF, PDCD8 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2
References: UniProt: O95831, Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors
#2: Protein Apoptosis-inducing factor 1, mitochondrial / / Programmed cell death protein 8


Mass: 59387.434 Da / Num. of mol.: 1 / Mutation: W196A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIFM1, AIF, PDCD8 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2
References: UniProt: O95831, Oxidoreductases; Acting on NADH or NADPH; With unknown physiological acceptors

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Non-polymers , 4 types, 185 molecules

#3: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE / Flavin adenine dinucleotide


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Comment: FAD*YM
#4: Chemical ChemComp-QBC / 7-chloroquinolin-4-amine


Mass: 178.618 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H7ClN2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 2.58 Å3/Da / Density % sol: 52.3 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 0.1 M Tris, pH 8.5, 0.3 M Na2SO4, 18% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.9793 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.51→29.36 Å / Num. obs: 43738 / % possible obs: 99.6 % / Redundancy: 10.4 % / Biso Wilson estimate: 51.24 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.084 / Rpim(I) all: 0.027 / Rrim(I) all: 0.089 / Net I/σ(I): 18.7
Reflection shellResolution: 2.51→2.61 Å / Rmerge(I) obs: 0.737 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 4401 / CC1/2: 0.906 / Rpim(I) all: 0.235 / Rrim(I) all: 0.774

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX1.18.2_3874refinement
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5KVH

5kvh


Resolution: 2.51→29.36 Å / SU ML: 0.279 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.1996
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2312 2145 4.91 %
Rwork0.2043 41516 -
obs0.2056 43661 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.67 Å2
Refinement stepCycle: LAST / Resolution: 2.51→29.36 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6488 0 134 180 6802
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00196763
X-RAY DIFFRACTIONf_angle_d0.49819189
X-RAY DIFFRACTIONf_chiral_restr0.04921033
X-RAY DIFFRACTIONf_plane_restr0.00261170
X-RAY DIFFRACTIONf_dihedral_angle_d10.21472376
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.570.31211340.27842624X-RAY DIFFRACTION95.04
2.57-2.630.2991500.25572696X-RAY DIFFRACTION100
2.63-2.70.2951260.24372772X-RAY DIFFRACTION99.9
2.7-2.780.24841430.23972711X-RAY DIFFRACTION99.93
2.78-2.870.27471750.23022749X-RAY DIFFRACTION99.97
2.87-2.980.27451450.23652723X-RAY DIFFRACTION99.97
2.98-3.10.28321490.24112750X-RAY DIFFRACTION100
3.1-3.240.30691440.2432759X-RAY DIFFRACTION100
3.24-3.410.25791530.21342737X-RAY DIFFRACTION99.97
3.41-3.620.21321310.20632776X-RAY DIFFRACTION99.97
3.62-3.90.23481310.19772797X-RAY DIFFRACTION100
3.9-4.290.1681540.17622787X-RAY DIFFRACTION99.97
4.29-4.910.1881510.16432795X-RAY DIFFRACTION99.97
4.91-6.170.23891380.20352855X-RAY DIFFRACTION100
6.17-29.360.21171210.19342985X-RAY DIFFRACTION99.68
Refinement TLS params.

Method: refined / 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)
11.244693748790.1907769093190.01298105905652.16510157537-0.7773089120810.8864154465090.04767529111740.0615308462667-0.152385822819-0.179834655020.08650728017630.3824747311730.12912981698-0.0883493303726-0.14539970620.394334955146-0.008616303949380.01334898190070.471367056445-0.008927263326720.397857204838-41.345-14.164-32.975
21.70600092846-0.161246636308-0.2571373468611.564000108440.260359948610.5707654195370.0348716401041-0.1543064415830.2413210326730.002094261801270.0551885290357-0.336398057799-0.05235552704790.0492232315154-0.09974692246440.364219970419-0.02956436407110.01213649636570.4419582550150.03758013644510.458947480222-1.5497.921-41.003
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN B AND ( RESID 127:617 OR RESID 701:701 ) )B127 - 617
2X-RAY DIFFRACTION1( CHAIN B AND ( RESID 127:617 OR RESID 701:701 ) )B701
3X-RAY DIFFRACTION2( CHAIN A AND ( RESID 129:611 OR RESID 701:702 OR RESID 801:883 ) ) OR ( CHAIN B AND RESID 839:839 )A129 - 611
4X-RAY DIFFRACTION2( CHAIN A AND ( RESID 129:611 OR RESID 701:702 OR RESID 801:883 ) ) OR ( CHAIN B AND RESID 839:839 )A701 - 702
5X-RAY DIFFRACTION2( CHAIN A AND ( RESID 129:611 OR RESID 701:702 OR RESID 801:883 ) ) OR ( CHAIN B AND RESID 839:839 )A801 - 883
6X-RAY DIFFRACTION2( CHAIN A AND ( RESID 129:611 OR RESID 701:702 OR RESID 801:883 ) ) OR ( CHAIN B AND RESID 839:839 )B839

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