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- PDB-8k72: Factor-inhibiting hypoxia-inducible factor in complex with Zn(II)... -

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Basic information

Entry
Database: PDB / ID: 8k72
TitleFactor-inhibiting hypoxia-inducible factor in complex with Zn(II) and 2-(3-hydroxy-2-((3-(phenylsulfonamido)propanoyl)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 / regulation of vascular endothelial growth factor receptor signaling pathway / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding ...hypoxia-inducible factor-asparagine dioxygenase / : / [protein]-asparagine 3-dioxygenase activity / peptidyl-histidine dioxygenase activity / peptidyl-aspartic acid 3-dioxygenase activity / regulation of vascular endothelial growth factor receptor signaling pathway / Cellular response to hypoxia / carboxylic acid binding / positive regulation of vasculogenesis / ankyrin repeat binding / Notch binding / oxygen sensor activity / 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 / cytosol / cytoplasm
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-VJF / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)42,01616
Polymers40,3281
Non-polymers1,68815
Water1,22568
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)84,03232
Polymers80,6572
Non-polymers3,37530
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_645y+1,x-1,-z1
Buried area7410 Å2
ΔGint-258 kcal/mol
Surface area31350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.610, 86.610, 145.050
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, 83 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / 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-VJF / 2-[(2~{Z})-3-oxidanyl-2-[3-(phenylsulfonylamino)propanoylimino]-1,3-thiazol-4-yl]ethanoic acid


Mass: 385.415 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15N3O6S2 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / 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: 3.37 Å3/Da / Density % sol: 63.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.27 mM FIH, 0.5 mM zinc acetate, 2 mM TC167, 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: Nov 20, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.45→72.53 Å / Num. obs: 21056 / % possible obs: 100 % / Redundancy: 26.5 % / Biso Wilson estimate: 72.14 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.168 / Net I/σ(I): 15.1
Reflection shellResolution: 2.45→2.49 Å / Redundancy: 25.6 % / Rmerge(I) obs: 5.078 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 1039 / CC1/2: 0.533 / % possible all: 99.9

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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: 2.45→61.24 Å / SU ML: 0.372 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.2521
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2386 1043 4.97 %
Rwork0.2 19936 -
obs0.2018 20979 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 92.83 Å2
Refinement stepCycle: LAST / Resolution: 2.45→61.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2798 0 43 68 2909
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00262943
X-RAY DIFFRACTIONf_angle_d0.5644008
X-RAY DIFFRACTIONf_chiral_restr0.043392
X-RAY DIFFRACTIONf_plane_restr0.0034523
X-RAY DIFFRACTIONf_dihedral_angle_d17.96521071
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.580.38591550.36232765X-RAY DIFFRACTION99.83
2.58-2.740.32821520.33712784X-RAY DIFFRACTION99.9
2.74-2.950.35831430.29042800X-RAY DIFFRACTION99.93
2.95-3.250.30661520.25722803X-RAY DIFFRACTION99.86
3.25-3.720.24841350.21492866X-RAY DIFFRACTION100
3.72-4.690.21071430.16252871X-RAY DIFFRACTION100
4.69-61.240.20071630.16863047X-RAY DIFFRACTION99.91
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)
10.976662484135-0.711971495296-0.4890937123370.4996459568560.3987481548970.316427857631-0.216873662953-0.325341896743-0.2238146559660.635450968821-0.3774662675540.8472336951810.443587441773-0.6551131086230.5568306064631.074315785480.03758467610360.2240470196710.824375963265-0.07190984007471.161608579310.8783008028-29.111345829422.3127324014
22.644542206320.8262006244730.5775549204834.113402690470.8029940025143.185860803260.08106755561490.3427062254780.4970044196210.132106858686-0.1394525847420.615591481-0.420975389959-0.08790878883980.0311180955140.7986699237610.1281601042780.1799857712850.5950401465440.02419630701940.80782290223219.4026933495-16.086453392314.0790892484
33.259690127940.574116444246-0.2422633445970.10826227237-0.03942327188250.0149066092291-0.4136762378871.265200787160.440092056448-0.3577864946140.238225101816-0.09155469707020.151446087806-0.5728583272720.2438730178211.191684196580.008192772992140.1213032726050.9930952506430.08902973754931.1128143854420.6245464319-31.5007114507-7.73135108064
41.038084794541.08480005924-0.8591965813644.10303482910.3846236722212.91591307614-0.1928177010420.773161744011.03317848018-0.862297361948-0.009583231295270.866081764663-0.597748149736-0.6604883247190.1974266715351.450830665950.368216278099-0.1718380904951.076541988470.1587106514211.074597425557.63558852362-14.8731524805-4.45965044731
50.993677160499-0.654051576129-0.6465902499843.662700465012.08744520962.774684349720.05880784296290.05484557762720.156918067506-0.0405464591960.07925386494190.22517461577-0.147131618781-0.0738835327913-0.1337137613460.7412010951160.04641749574950.1136357592390.5602419453950.03405075007030.74620496681821.5343119855-26.57967511659.74496443802
63.6535122147-1.47050480573-1.271409603156.896167745420.2949391526862.53527009915-0.0876717611591-0.06149580299120.697483963091-0.2628556209640.270991224143-0.408437088716-0.06252630404770.256116784722-0.1989749066020.628235094786-0.01927550904470.02300031310560.7710145634250.001046812200070.75761698066739.9567746081-41.32410076222.60224997821
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 95 )
3X-RAY DIFFRACTION3chain 'A' and (resid 96 through 119 )
4X-RAY DIFFRACTION4chain 'A' and (resid 120 through 138 )
5X-RAY DIFFRACTION5chain 'A' and (resid 139 through 297 )
6X-RAY DIFFRACTION6chain 'A' and (resid 298 through 349 )

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