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- PDB-5op6: Factor Inhibiting HIF (FIH) in complex with zinc and GSK128863 -

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Basic information

Entry
Database: PDB / ID: 5op6
TitleFactor Inhibiting HIF (FIH) in complex with zinc and GSK128863
ComponentsHypoxia-inducible factor 1-alpha inhibitor
KeywordsOXIDOREDUCTASE / ON-HEME / DIOXYGENASE / OXYGENASE / DNA-BINDING / METAL-BINDING / TRANSCRIPTION / HELIX-LOOP-HELIX-BETA / DSBH / FACIAL TRIAD / ASPARAGINYL/ASPARTYL HYDROXYLASE / EPIGENETIC REGULATION / SIGNALING / ARD / BETA-HYDROXYLATION / ACTIVATOR-INHIBITOR / OXIDOREDUCTASE-PEPTIDE COMPLEX
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
Clavaminate synthase-like / 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. / Jelly Rolls / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold / Helix Hairpins ...Clavaminate synthase-like / 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. / Jelly Rolls / JmjC domain / JmjC domain profile. / RmlC-like jelly roll fold / Helix Hairpins / Jelly Rolls / Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Chem-A0W / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsLeissing, T.M. / Schofield, C.J. / Clifton, I.J. / Thinnes, C.C. / Lu, X.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Engineering and Physical Sciences Research CouncilG03706X/1 United Kingdom
CitationJournal: Chem Sci / Year: 2017
Title: Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials.
Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I. ...Authors: Yeh, T.L. / Leissing, T.M. / Abboud, M.I. / Thinnes, C.C. / Atasoylu, O. / Holt-Martyn, J.P. / Zhang, D. / Tumber, A. / Lippl, K. / Lohans, C.T. / Leung, I.K.H. / Morcrette, H. / Clifton, I.J. / Claridge, T.D.W. / Kawamura, A. / Flashman, E. / Lu, X. / Ratcliffe, P.J. / Chowdhury, R. / Pugh, C.W. / Schofield, C.J.
History
DepositionAug 9, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 18, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 17, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)41,2976
Polymers40,5541
Non-polymers7435
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area590 Å2
ΔGint-27 kcal/mol
Surface area16190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.210, 86.210, 147.070
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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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: 40553.500 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 (E. coli)
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, 51 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-A0W / 2-[[1,3-dicyclohexyl-4-oxidanyl-2,6-bis(oxidanylidene)pyrimidin-5-yl]carbonylamino]ethanoic acid


Mass: 393.434 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27N3O6
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O

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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: 63.49 % / Description: Tetragonal bipyramid
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M HEPES pH7.5, 1.1M ammonium sulfate, 2.5% PEG 400
Temp details: ambient

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryo cooled
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.45→30.48 Å / Num. obs: 21126 / % possible obs: 100 % / Redundancy: 11.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.138 / Rpim(I) all: 0.042 / Net I/σ(I): 11.5
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 11.1 % / Rmerge(I) obs: 1.25 / Mean I/σ(I) obs: 2 / Num. unique obs: 3014 / CC1/2: 0.57 / Rpim(I) all: 0.39 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.10_2155: ???)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1h2k

1h2k


Resolution: 2.45→30.305 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 22.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2274 1051 4.99 %
Rwork0.2037 --
obs0.2049 21064 99.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.45→30.305 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2619 0 45 46 2710
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052747
X-RAY DIFFRACTIONf_angle_d0.5693744
X-RAY DIFFRACTIONf_dihedral_angle_d11.3351597
X-RAY DIFFRACTIONf_chiral_restr0.043385
X-RAY DIFFRACTIONf_plane_restr0.003492
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4501-2.56160.30871210.2972432X-RAY DIFFRACTION100
2.5616-2.69650.29251350.2722470X-RAY DIFFRACTION100
2.6965-2.86540.26821290.24472452X-RAY DIFFRACTION100
2.8654-3.08640.25441260.22542459X-RAY DIFFRACTION100
3.0864-3.39660.27461380.22182474X-RAY DIFFRACTION100
3.3966-3.88730.22071550.18812475X-RAY DIFFRACTION100
3.8873-4.89420.17891290.162548X-RAY DIFFRACTION100
4.8942-30.30740.21311180.20462703X-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)
10.5481-0.5479-0.09790.8565-0.33070.5255-0.27080.64760.7613-0.1511-0.16190.2124-0.38030.4149-0.00070.48530.0106-0.06390.7840.25130.7352-13.642832.4798-22.1098
21.27860.63930.73151.2901-0.73721.6622-0.03850.54040.1209-0.38780.2210.24530.0693-0.1341-00.39650.0697-0.03270.76130.14440.4507-23.172620.3848-22.5961
30.5336-0.1749-0.02010.2460.23230.17580.0479-1.12990.2040.5546-0.35620.35310.0339-1.12480.00260.61770.12830.08531.1074-0.11260.7035-32.550729.8186-1.4789
40.1281-0.18720.05050.49310.01310.036-0.3302-0.58320.11781.4055-0.1822-0.499-0.6284-0.3982-0.00220.7109-0.08550.01911.19890.14020.6792-14.51923.30167.1377
50.4131-0.60050.40261.0441-0.70230.5245-0.139-1.30260.52360.8397-0.1712-0.2475-0.6491-1.33450.00180.70.22770.15471.3986-0.08750.7012-27.175532.71240.6752
63.3487-0.64652.09620.5129-0.43452.99830.0909-0.11940.18520.13320.00310.092-0.0053-0.17980.00610.32040.02460.01610.60850.13070.474-15.103321.2443-11.0409
71.4991-0.92490.23951.978-0.63390.3490.0947-0.0933-0.2058-0.0752-0.09020.36840.317-0.337300.5873-0.0201-0.10820.58170.04630.5451-1.6333.5458-2.663
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 15 through 49 )
2X-RAY DIFFRACTION2chain 'A' and (resid 50 through 77 )
3X-RAY DIFFRACTION3chain 'A' and (resid 78 through 95 )
4X-RAY DIFFRACTION4chain 'A' and (resid 96 through 124 )
5X-RAY DIFFRACTION5chain 'A' and (resid 125 through 155 )
6X-RAY DIFFRACTION6chain 'A' and (resid 156 through 297 )
7X-RAY DIFFRACTION7chain 'A' and (resid 298 through 349 )

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