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- PDB-8ihz: FACTOR INHIBITING HIF-1 ALPHA in complex with (5-(1-(3-(4-chlorop... -

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Basic information

Entry
Database: PDB / ID: 8ihz
TitleFACTOR INHIBITING HIF-1 ALPHA in complex with (5-(1-(3-(4-chlorophenyl)propyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypicolinoyl)glycine
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
: / Hypoxia-inducible factor 1-alpha inhibitor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsNakashima, Y. / Corner, T. / Zhang, X. / Schofield, C.J.
Funding support China, United Kingdom, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81973173 China
Wellcome Trust106244/Z/14/Z United Kingdom
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2024
Title: A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-flip Pocket for the Treatment of Obesity.
Authors: Wu, Y. / Chen, Y. / Corner, T. / Nakashima, Y. / Salah, E. / Li, Z. / Zhang, L. / Yang, L. / Tumber, A. / Sun, Z. / Wen, Y. / Zhong, A. / Yang, F. / Li, X. / Zhang, Z. / Schofield, C. / Zhang, X.
History
DepositionFeb 24, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)42,15417
Polymers40,3281
Non-polymers1,82616
Water1,38777
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)86.578, 86.578, 147.416
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.: 14 / 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-P1X / 2-[[5-[1-[3-(4-chlorophenyl)propyl]-1,2,3-triazol-4-yl]-3-oxidanyl-pyridin-2-yl]carbonylamino]ethanoic acid / (5-(1-(3-(4-chlorophenyl)propyl)-1H-1,2,3-triazol-4-yl)-3-hydroxypicolinoyl)glycine


Mass: 415.830 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18ClN5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 77 / Source method: isolated from a natural source / Formula: H2O
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: 3.42 Å3/Da / Density % sol: 64.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 1.6 M AMMONIUM SULPHATE, 6% PEG 400, 0.1 M HEPES

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97624 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 4, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97624 Å / Relative weight: 1
ReflectionResolution: 2.22→74.65 Å / Num. obs: 28505 / % possible obs: 100 % / Redundancy: 25.6 % / Biso Wilson estimate: 73.37 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.092 / Net I/σ(I): 20
Reflection shellResolution: 2.22→2.26 Å / Redundancy: 26.6 % / Rmerge(I) obs: 5.601 / Mean I/σ(I) obs: 0.3 / Num. unique obs: 1381 / CC1/2: 0.285 / % 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: 1H2K

1h2k


Resolution: 2.22→61.22 Å / SU ML: 0.3589 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 29.5713
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2613 1924 7.06 %
Rwork0.2267 25319 -
obs0.2291 27243 95.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 96.82 Å2
Refinement stepCycle: LAST / Resolution: 2.22→61.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2755 0 65 77 2897
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00922905
X-RAY DIFFRACTIONf_angle_d1.08833966
X-RAY DIFFRACTIONf_chiral_restr0.054393
X-RAY DIFFRACTIONf_plane_restr0.0068516
X-RAY DIFFRACTIONf_dihedral_angle_d20.49931033
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.22-2.280.3911860.3865999X-RAY DIFFRACTION54.3
2.28-2.340.35261180.37011593X-RAY DIFFRACTION86.41
2.34-2.410.36571390.34491843X-RAY DIFFRACTION99.95
2.41-2.480.31791410.31551861X-RAY DIFFRACTION99.85
2.48-2.570.26691390.30641831X-RAY DIFFRACTION99.95
2.57-2.680.32661420.3061884X-RAY DIFFRACTION100
2.68-2.80.32341420.30041862X-RAY DIFFRACTION99.9
2.8-2.940.35571410.30931862X-RAY DIFFRACTION99.95
2.94-3.130.37161410.27761873X-RAY DIFFRACTION99.9
3.13-3.370.27481420.25721879X-RAY DIFFRACTION100
3.37-3.710.27211440.23261906X-RAY DIFFRACTION99.95
3.71-4.250.22781450.19341908X-RAY DIFFRACTION100
4.25-5.350.18711480.17471948X-RAY DIFFRACTION99.95
5.35-61.220.28391560.21842070X-RAY DIFFRACTION99.96
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)
10.192055566484-0.177934217549-0.154663785922-0.0103590063331-0.01173558915750.2288270531960.527174023779-0.04612528896353.04020695892-0.1405890310430.510485327884-1.21836907248-2.748633711791.210219856221.54850661086E-60.4518655894770.319364908563-0.7641910270720.338079571730.05286237707560.614753136655.1336423648628.451932798213.5031420042
20.4199544861930.2518252170790.1911419054130.3302346111250.4372236531880.483156042692-0.004986942688680.128344265022-0.0550795003755-0.6216172850270.03030427613880.3488403325650.0343540632520.0002208451041895.45976380558E-90.933284625805-0.0841617554014-0.1837046707310.6095561687870.01742590433110.67694966611720.209036690325.297026760514.6281283749
30.644894863977-1.19199462579-0.5222506332010.631862597894-0.2499974110130.3149780617320.188277621619-0.358467920752-0.173978719883-0.665597537111-1.422251002941.73935282991-0.118238574676-1.08262240765-7.06513849128E-90.661357468999-0.2415644749250.1989156101290.1651433836330.383423757426-0.19242849024516.872005428922.24436964940.7348845405
40.4957187363890.362162263530.7174699759960.9725517558710.006797770408530.5048501714740.206249040441-0.269228000857-0.343080299560.371311354702-0.0811040810974-0.05574045343690.4643580642520.109447094342-3.19324965645E-80.974621859909-0.0709636375779-0.09065861843780.592322344820.02980279143710.69487828701919.227734822414.884358610229.2901388421
50.3503335133160.3732620302850.4988969173620.7581140448070.1598702061251.15052019119-0.0465374758875-0.0352182003966-0.0161279626317-0.04386654773540.101289199660.1410053130590.04309120695460.09488306625431.84151622815E-100.665792195355-0.00243720340588-0.0683437830020.530815270461-0.026870430180.60806830702226.061454320435.687588652929.1092009309
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 77 )
3X-RAY DIFFRACTION3chain 'A' and (resid 78 through 124 )
4X-RAY DIFFRACTION4chain 'A' and (resid 125 through 190 )
5X-RAY DIFFRACTION5chain 'A' and (resid 191 through 349 )

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