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- PDB-9iif: Factor inhibiting HIF-1 alpha in complex with Zn(II) and Desidustat -

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Basic information

Entry
Database: PDB / ID: 9iif
TitleFactor inhibiting HIF-1 alpha in complex with Zn(II) and Desidustat
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
: / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsNakashima, Y. / Corner, T.P. / Brewitz, L. / Schofield, C.J.
Funding support United Kingdom, 4items
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
Wellcome Trust106244/Z/14/Z United Kingdom
Cancer Research UKC8717/A18245 United Kingdom
CitationJournal: Chemmedchem / Year: 2024
Title: Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.
Authors: Corner, T.P. / Salah, E. / Tumber, A. / Kaur, S. / Nakashima, Y. / Allen, M.D. / Schnaubelt, L.I. / Fiorini, G. / Brewitz, L. / Schofield, C.J.
History
DepositionJun 20, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 29, 2025Provider: 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)41,49511
Polymers40,3281
Non-polymers1,16610
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-16 kcal/mol
Surface area17120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.561, 86.561, 144.824
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

#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
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: SO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-A1L2L / 2-[[1-(cyclopropylmethoxy)-2-oxidanyl-4-oxidanylidene-quinolin-3-yl]carbonylamino]ethanoic acid


Mass: 332.308 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N2O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.36 Å3/Da / Density % sol: 63.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.27 mM FIH, 0.5 mM zinc acetate, 2 mM densidustat, 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: 0.97627 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jan 26, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97627 Å / Relative weight: 1
ReflectionResolution: 2.16→56.35 Å / Num. obs: 53587 / % possible obs: 100 % / Redundancy: 26.5 % / Biso Wilson estimate: 67.49 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.081 / Net I/σ(I): 20.8
Reflection shellResolution: 2.16→2.2 Å / Redundancy: 27 % / Rmerge(I) obs: 5.228 / Mean I/σ(I) obs: 0.3 / Num. unique obs: 1473 / CC1/2: 0.278 / % 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 / Resolution: 2.16→43.28 Å / SU ML: 0.3906 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.5321
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2437 2628 4.9 %
Rwork0.1951 50959 -
obs0.1974 53587 95.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 97.08 Å2
Refinement stepCycle: LAST / Resolution: 2.16→43.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2790 0 44 46 2880
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00542909
X-RAY DIFFRACTIONf_angle_d0.7473957
X-RAY DIFFRACTIONf_chiral_restr0.0495391
X-RAY DIFFRACTIONf_plane_restr0.0058518
X-RAY DIFFRACTIONf_dihedral_angle_d21.33741070
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.16-2.20.3111140.4398404X-RAY DIFFRACTION14.18
2.2-2.240.39791390.40242598X-RAY DIFFRACTION92.87
2.24-2.290.40991510.37612806X-RAY DIFFRACTION99.56
2.29-2.340.42241360.35312845X-RAY DIFFRACTION99.9
2.34-2.390.37411520.31432807X-RAY DIFFRACTION99.93
2.39-2.450.27381530.27812810X-RAY DIFFRACTION99.76
2.45-2.520.3111530.26952821X-RAY DIFFRACTION99.87
2.52-2.590.25471650.25192774X-RAY DIFFRACTION99.93
2.59-2.680.28181530.25312813X-RAY DIFFRACTION100
2.68-2.770.31581390.25072844X-RAY DIFFRACTION99.93
2.77-2.880.34111290.23242842X-RAY DIFFRACTION100
2.88-3.010.25871440.2152825X-RAY DIFFRACTION100
3.01-3.170.2971500.2222803X-RAY DIFFRACTION100
3.17-3.370.27811270.22782842X-RAY DIFFRACTION100
3.37-3.630.24521550.17932809X-RAY DIFFRACTION100
3.63-40.25811390.17922823X-RAY DIFFRACTION100
4-4.570.17961520.15252836X-RAY DIFFRACTION100
4.57-5.760.20491460.16262819X-RAY DIFFRACTION100
5.76-43.280.23371310.18082838X-RAY DIFFRACTION100
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)
11.37737879373-0.3085936635940.08189176228180.05006381565810.04243853705480.0801660786914-0.102458681722-0.493621339853-0.2397732522040.918696104327-0.1983883578090.9077698634490.170512800892-0.7185737848320.2702352567831.217182676670.06083533801720.3720412343610.796878213861-0.02542679096721.0398968371710.5212211818-29.641665056322.1793451423
22.380656182920.1442244197560.01180426317872.432377085581.354347799881.61486849518-0.04592495558050.4304892856230.241192400853-0.492728730719-0.07185289571510.256959220389-0.422255716961-0.2337745482810.07664582635341.16734748380.09906344154940.04126853634020.6404803859370.09174859397480.73696011582517.0235033642-20.13456266543.81391434353
31.119686708020.1783326639470.9762636234873.825325704851.404451498444.10903030608-0.1022979096490.6179762259740.52842045275-0.9077588648980.06961964388820.444880513332-1.230990639760.2469706084380.08846042414821.257118544230.1040122355450.1424002210530.6954006231640.09028776471890.82176650753117.7690200595-11.54630749915.44457040061
41.22120547484-1.35951227333-0.9547663401782.96822038731.716986293922.04051398621-0.02213835716680.03123775523310.2464985684250.1977426492980.1946631670470.0358615329565-0.1767526199790.183067300037-0.160271746670.75824906961-0.004391417547580.1224691696760.4582584093320.009425871582030.59452446447626.8057282249-32.71181423158.49777041157
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 49 )
2X-RAY DIFFRACTION2chain 'A' and (resid 50 through 138 )
3X-RAY DIFFRACTION3chain 'A' and (resid 139 through 166 )
4X-RAY DIFFRACTION4chain 'A' and (resid 167 through 349 )

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