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- PDB-5opc: Factor Inhibiting HIF (FIH) in complex with zinc and Vadadustat -

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Basic information

Entry
Database: PDB / ID: 5opc
TitleFactor Inhibiting HIF (FIH) in complex with zinc and Vadadustat
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 / Notch binding ...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 / 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
Clavaminate synthase-like / Hypoxia-inducible factor 1-alpha inhibitor, domain II / Cupin-like domain 8 / Cupin-like domain / Jelly Rolls / A domain family that is part of the cupin metalloenzyme superfamily. / 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 / Jelly Rolls / A domain family that is part of the cupin metalloenzyme superfamily. / 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
Vadadustat / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLeissing, T.M. / Schofield, C.J. / Clifton, I.J. / Lu, X. / Zhang, D.
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)41,72813
Polymers40,4151
Non-polymers1,31312
Water1,29772
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)83,45726
Polymers80,8312
Non-polymers2,62624
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_465y-1,x+1,-z1
Buried area6480 Å2
ΔGint-203 kcal/mol
Surface area30100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.799, 86.799, 149.520
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: 40415.355 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, 84 molecules

#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-A1Z / Vadadustat / GSK128863


Mass: 306.701 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11ClN2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 72 / 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: 3.48 Å3/Da / Density % sol: 64.7 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1M HEPES pH7.5, 1.7M ammonium sulfate, 5.5% PEG 400
Temp details: ambient

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: cryo cooling
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.3→86.8 Å / Num. obs: 26216 / % possible obs: 100 % / Redundancy: 17.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.036 / Net I/σ(I): 10.9
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 17.5 % / Rmerge(I) obs: 1.78 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 3748 / CC1/2: 0.689 / Rpim(I) all: 0.435 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829)refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1h2k

1h2k


Resolution: 2.3→75.067 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.33
RfactorNum. reflection% reflection
Rfree0.214 1294 4.95 %
Rwork0.1925 --
obs0.1936 26128 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.3→75.067 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2672 0 77 72 2821
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0032827
X-RAY DIFFRACTIONf_angle_d0.5223849
X-RAY DIFFRACTIONf_dihedral_angle_d9.9721636
X-RAY DIFFRACTIONf_chiral_restr0.044387
X-RAY DIFFRACTIONf_plane_restr0.004504
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.39210.34981390.28372703X-RAY DIFFRACTION100
2.3921-2.5010.28421500.242695X-RAY DIFFRACTION100
2.501-2.63280.25091300.22112721X-RAY DIFFRACTION100
2.6328-2.79780.23891380.2072733X-RAY DIFFRACTION100
2.7978-3.01380.26511360.20192708X-RAY DIFFRACTION100
3.0138-3.31710.20661600.18732738X-RAY DIFFRACTION100
3.3171-3.79710.19151300.17022773X-RAY DIFFRACTION100
3.7971-4.78380.15721540.15612798X-RAY DIFFRACTION100
4.7838-75.1070.24061570.21522965X-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)
10.4083-0.6003-0.35680.82890.51130.4169-0.23780.7149-0.9245-0.3577-0.34980.00960.5241-0.31150.56960.65070.02870.06930.9675-0.32280.8163-30.142910.9083-23.1524
23.1108-0.647-1.86762.49610.21852.7090.0613-0.2631-0.29620.0524-0.1625-0.10640.03890.37810.11570.33630.0299-0.0760.8146-0.15150.5421-19.437518.6425-12.0238
32.2208-1.9452-0.80032.88310.35690.3878-0.4586-1.0445-0.27530.75360.19560.43110.48880.65470.20160.89780.2348-0.08931.11750.04880.6388-22.647613.48254.5359
42.4408-1.1561-1.51541.75050.63990.91790.2097-0.58190.64180.16290.0676-0.7105-0.38930.9671-0.12890.4503-0.0546-0.02520.9186-0.18970.6152-12.668926.9516-14.1978
52.2854-0.8325-2.14350.38811.19963.70950.0315-0.0423-0.26730.1250.0393-0.1287-0.01590.1191-0.07560.33330.0076-0.00680.6024-0.130.5215-33.678421.4573-8.2104
61.7184-1.5158-1.10232.54210.23882.46740.10280.385-0.19540.0324-0.1473-0.09780.1204-0.12230.03350.28370.0026-0.01840.6566-0.15020.4417-32.557219.399-12.8471
72.6464-0.6530.43922.04120.49870.59710.28660.03290.4829-0.23810.0866-0.5655-0.53340.197-0.31520.5919-0.0090.14790.5777-0.07620.6746-36.175340.6013-7.0205
84.2743-0.46820.05454.4979-0.76962.86020.2541-0.2315-0.1420.4075-0.08440.28770.47960.5678-0.06940.65350.09280.08080.5114-0.05940.4622-50.147238.12945.2855
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 104 )
3X-RAY DIFFRACTION3chain 'A' and (resid 105 through 149 )
4X-RAY DIFFRACTION4chain 'A' and (resid 150 through 190 )
5X-RAY DIFFRACTION5chain 'A' and (resid 191 through 246 )
6X-RAY DIFFRACTION6chain 'A' and (resid 247 through 297 )
7X-RAY DIFFRACTION7chain 'A' and (resid 298 through 329 )
8X-RAY DIFFRACTION8chain 'A' and (resid 330 through 349 )

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