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- PDB-8k73: Factor-inhibiting hypoxia-inducible factor in complex with Zn(II)... -

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Basic information

Entry
Database: PDB / ID: 8k73
TitleFactor-inhibiting hypoxia-inducible factor in complex with Zn(II) and 2-(3-hydroxy-2-((1-(phenylsulfonyl)pyrrolidine-3-carbonyl)imino)-2,3-dihydrothiazol-4-yl)acetic acid
ComponentsHypoxia-inducible factor 1-alpha inhibitor
KeywordsOXIDOREDUCTASE / factor-inhibiting hypoxia-inducible factor / FIH / 2OG dependent dioxygenase
Function / homology
Function and homology information


hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding / oxygen sensor activity ...hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding / oxygen sensor activity / Notch binding / negative regulation of Notch signaling pathway / NF-kappaB binding / positive regulation of myoblast differentiation / ferrous iron binding / transcription corepressor activity / perinuclear region of cytoplasm / protein homodimerization activity / zinc ion binding / nucleoplasm / cytoplasm / cytosol
Similarity search - Function
Hypoxia-inducible factor 1-alpha inhibitor, domain II / Cupin-like domain 8 / Cupin-like domain / A domain family that is part of the cupin metalloenzyme superfamily. / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold
Similarity search - Domain/homology
Chem-VK6 / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsNakashima, Y. / Corner, T.P. / Teo, R.Z.R. / Brewitz, L. / Schofield, C.J.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC)BB/J003018/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/R000344/1 United Kingdom
CitationJournal: Chem Sci / Year: 2023
Title: Structure-guided optimisation of N -hydroxythiazole-derived inhibitors of factor inhibiting hypoxia-inducible factor-alpha.
Authors: Corner, T.P. / Teo, R.Z.R. / Wu, Y. / Salah, E. / Nakashima, Y. / Fiorini, G. / Tumber, A. / Brasnett, A. / Holt-Martyn, J.P. / Figg Jr., W.D. / Zhang, X. / Brewitz, L. / Schofield, C.J.
History
DepositionJul 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,12217
Polymers40,3281
Non-polymers1,79416
Water1,45981
1
A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules

A: Hypoxia-inducible factor 1-alpha inhibitor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,24434
Polymers80,6572
Non-polymers3,58832
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_645y+1,x-1,-z1
Buried area8550 Å2
ΔGint-218 kcal/mol
Surface area31290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.609, 86.609, 145.259
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Hypoxia-inducible factor 1-alpha inhibitor / Factor inhibiting HIF-1 / FIH-1 / Hypoxia-inducible factor asparagine hydroxylase


Mass: 40328.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HIF1AN, FIH1 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one ...References: UniProt: Q9NWT6, hypoxia-inducible factor-asparagine dioxygenase, Oxidoreductases; Acting on paired donors, with incorporation or reduction of molecular oxygen; With 2-oxoglutarate as one donor, and incorporation of one atom of oxygen into each donor

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Non-polymers , 5 types, 97 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-VK6 / 2-[(2~{Z})-3-oxidanyl-2-[(3~{R})-1-(phenylsulfonyl)pyrrolidin-3-yl]carbonylimino-1,3-thiazol-4-yl]ethanoic acid


Mass: 411.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17N3O6S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 3.38 Å3/Da / Density % sol: 63.58 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.27 mM FIH, 0.5 mM zinc acetate, 2 mM RT105, 0.1 M HEPES, pH 7.5, 6%w/v PEG400, 1.6 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Apr 28, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.02→74.39 Å / Num. obs: 66833 / % possible obs: 100 % / Redundancy: 26.5 % / Biso Wilson estimate: 58.62 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.079 / Net I/σ(I): 21.8
Reflection shellResolution: 2.02→2.05 Å / Redundancy: 26.6 % / Rmerge(I) obs: 4.74 / Mean I/σ(I) obs: 0.3 / Num. unique obs: 1797 / CC1/2: 0.364 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4B7K

4b7k


Resolution: 2.02→61.24 Å / SU ML: 0.3699 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.3099
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2227 3375 5.05 %
Rwork0.201 63458 -
obs0.2021 66833 96.55 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 76.54 Å2
Refinement stepCycle: LAST / Resolution: 2.02→61.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2795 0 52 81 2928
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00272990
X-RAY DIFFRACTIONf_angle_d0.58944069
X-RAY DIFFRACTIONf_chiral_restr0.0445396
X-RAY DIFFRACTIONf_plane_restr0.0041533
X-RAY DIFFRACTIONf_dihedral_angle_d16.77111097
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.02-2.050.4625660.43161424X-RAY DIFFRACTION52.13
2.05-2.080.3792750.42111889X-RAY DIFFRACTION68.1
2.08-2.110.40291250.40412763X-RAY DIFFRACTION98.4
2.11-2.150.39411600.38732648X-RAY DIFFRACTION99.36
2.15-2.180.40741730.37312703X-RAY DIFFRACTION99.72
2.18-2.220.3621420.35132777X-RAY DIFFRACTION100
2.22-2.270.30691630.35772710X-RAY DIFFRACTION99.97
2.27-2.310.3621090.30352772X-RAY DIFFRACTION99.86
2.31-2.360.31171440.28382724X-RAY DIFFRACTION99.97
2.36-2.420.25571610.2632741X-RAY DIFFRACTION99.79
2.42-2.480.28721530.24282705X-RAY DIFFRACTION99.93
2.48-2.540.26261410.24042757X-RAY DIFFRACTION100
2.54-2.620.31471490.2622726X-RAY DIFFRACTION99.9
2.62-2.70.30011420.26912741X-RAY DIFFRACTION100
2.7-2.80.25821790.25722702X-RAY DIFFRACTION99.97
2.8-2.910.22741600.22542751X-RAY DIFFRACTION100
2.91-3.050.22561290.2292716X-RAY DIFFRACTION100
3.05-3.210.27141460.23522753X-RAY DIFFRACTION100
3.21-3.410.24191220.22442769X-RAY DIFFRACTION100
3.41-3.670.19551470.19012744X-RAY DIFFRACTION100
3.67-4.040.22491450.18042742X-RAY DIFFRACTION100
4.04-4.620.181460.14452713X-RAY DIFFRACTION100
4.62-5.820.16291420.15072766X-RAY DIFFRACTION100
5.83-61.240.19271560.16552722X-RAY DIFFRACTION99.86
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)
10.434045613699-0.554407466395-0.5808099028320.6439997853550.7482668198180.765337151228-0.100219227193-0.2905343494590.009998755193270.759808857806-0.3288524788080.9620558018050.292410873888-0.6176058982470.3705611359640.8379722704590.02729161384850.2701172123040.583759349719-0.06512349896930.81132883058710.5983303209-29.50238492221.9742249564
21.9688375152-0.2976756702380.1695074612813.28457883689-0.034980303392.494289697330.039528930884-0.392477297920.26713175420.4911696485810.158774233191-0.0790771223601-0.107773574925-0.0218728493354-0.1373617289130.8674951730710.050730163280.1470886127830.501414502959-0.03308382582990.56305895169123.0151090695-19.751688771522.4146636176
32.75858362209-0.48289753349-0.04997451718511.34918707501-0.06784857699040.6625214506450.02056289568940.7958010787630.105942096019-0.824847348855-0.2450252051230.14053022813-0.510561689636-0.3001776115080.2193395791641.056757356320.0946635878931-0.05269298158720.7811650258640.1523358464090.64811138655117.5325497602-22.2869684975-3.85100531301
41.27382852968-0.318538587967-0.5292790744982.964015748411.661550977582.7717308799-0.000599187680230.1709422506190.114452884733-0.1403778756870.04158040700760.263190980788-0.31460025701-0.0929434887593-0.05880747638480.6550127475420.03669378025830.09207913745740.4276517843280.04232744015940.5258443356120.3197208242-25.47341077047.87075044341
51.208777614880.212280780102-0.5849143311422.719182809170.7713383729252.180268013360.1569860527660.121535480909-0.1068234831670.1190230774250.148486181198-0.215876615524-0.2335678029110.327498354953-0.2897820878980.6576911671350.02869701176660.06099383832960.547253393899-0.02868762604230.696762186129.5500791078-26.132728470613.0181640659
61.93153500133-0.866157248772-0.4421028499852.719768938640.2131093984172.28227048455-0.02189071867820.1597752216840.4702494273-0.217147059513-0.0263134726855-0.206767943954-0.3330452112420.2242618571940.02800309156110.585984928586-0.01963676489550.03538547155580.599939161516-0.03445080788560.52822191259838.7474626848-43.7465163248-1.63531159079
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 49 )
2X-RAY DIFFRACTION2chain 'A' and (resid 50 through 77 )
3X-RAY DIFFRACTION3chain 'A' and (resid 78 through 119 )
4X-RAY DIFFRACTION4chain 'A' and (resid 120 through 283 )
5X-RAY DIFFRACTION5chain 'A' and (resid 284 through 311 )
6X-RAY DIFFRACTION6chain 'A' and (resid 312 through 349 )

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