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- PDB-7ump: CRYSTAL STRUCTURE OF PHD2 CATALYTIC DOMAIN (CID 7465) IN COMPLEX ... -

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Basic information

Entry
Database: PDB / ID: 7ump
TitleCRYSTAL STRUCTURE OF PHD2 CATALYTIC DOMAIN (CID 7465) IN COMPLEX WITH AKB-6548 AT 1.8 A RESOLUTION
ComponentsEgl nine homolog 1
KeywordsOXIDOREDUCTASE / METAL BINDING PROTEIN / EGLN1 / PHD2
Function / homology
Function and homology information


peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / peptidyl-proline dioxygenase activity / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis / heart trabecula formation ...peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / peptidyl-proline dioxygenase activity / negative regulation of cyclic-nucleotide phosphodiesterase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / labyrinthine layer development / cardiac muscle tissue morphogenesis / heart trabecula formation / regulation of modification of postsynaptic structure / 2-oxoglutarate-dependent dioxygenase activity / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / regulation of angiogenesis / ferrous iron binding / negative regulation of DNA-binding transcription factor activity / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cellular response to hypoxia / intracellular iron ion homeostasis / postsynaptic density / response to hypoxia / intracellular membrane-bounded organelle / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleus / cytosol / cytoplasm
Similarity search - Function
: / Prolyl 4-hydroxylase alpha subunit, Fe(2+) 2OG dioxygenase domain / 2OG-Fe(II) oxygenase superfamily / Prolyl 4-hydroxylase, alpha subunit / Prolyl 4-hydroxylase alpha subunit homologues. / MYND finger / Zinc finger, MYND-type / Zinc finger MYND-type signature. / Zinc finger MYND-type profile. / Oxoglutarate/iron-dependent dioxygenase / Fe(2+) 2-oxoglutarate dioxygenase domain profile.
Similarity search - Domain/homology
Vadadustat / : / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDavie, D.R. / Abendroth, J. / Boyd, J.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Pharmacol.Exp.Ther. / Year: 2022
Title: Preclinical Characterization of Vadadustat (AKB-6548), an Oral Small Molecule Hypoxia-Inducible Factor Prolyl-4-Hydroxylase Inhibitor, for the Potential Treatment of Renal Anemia.
Authors: Zuk, A. / Si, Z. / Loi, S. / Bommegowda, S. / Hoivik, D. / Danthi, S. / Molnar, G. / Csizmadia, V. / Rabinowitz, M.
History
DepositionApr 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Jun 1, 2022Group: Database references / Structure summary / Category: citation / citation_author / struct
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _citation.year / _struct.title
Revision 1.2Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed ..._citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.3Dec 21, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.4Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Egl nine homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,7524
Polymers24,3281
Non-polymers4253
Water2,324129
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)111.400, 111.400, 40.420
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Egl nine homolog 1 / Hypoxia-inducible factor prolyl hydroxylase 2 / HIF-PH2 / HIF-prolyl hydroxylase 2 / HPH-2 / Prolyl ...Hypoxia-inducible factor prolyl hydroxylase 2 / HIF-PH2 / HIF-prolyl hydroxylase 2 / HPH-2 / Prolyl hydroxylase domain-containing protein 2 / PHD2 / SM-20


Mass: 24327.801 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGLN1, C1orf12, PNAS-118, PNAS-137 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9GZT9, hypoxia-inducible factor-proline dioxygenase
#2: Chemical ChemComp-FE2 / FE (II) ION


Mass: 55.845 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Fe / Feature type: SUBJECT OF INVESTIGATION
#3: 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
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 129 / 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: 2.97 Å3/Da / Density % sol: 58.61 %
Crystal growTemperature: 299 K / Method: vapor diffusion / pH: 5.5
Details: 100 MM SODIUM ACETATE PH 5.5, 21% PEG1500, 15% MPD, 300 MM MGSO4, 4 MM AKB-6548
PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97856 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jul 20, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 26873 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 7.29 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 20.6
Reflection shellResolution: 1.8→1.85 Å / Rmerge(I) obs: 0.503 / Mean I/σ(I) obs: 3.47 / Num. unique obs: 1644 / % possible all: 100

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX(1.12_2829)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OUH

3ouh


Resolution: 1.8→32.71 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / Phase error: 17.65
RfactorNum. reflection% reflection
Rfree0.202 2051 7.64 %
Rwork0.169 --
obs-26856 100 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→32.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1656 0 25 129 1810
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071751
X-RAY DIFFRACTIONf_angle_d0.9062379
X-RAY DIFFRACTIONf_dihedral_angle_d12.8341014
X-RAY DIFFRACTIONf_chiral_restr0.061250
X-RAY DIFFRACTIONf_plane_restr0.006314
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8001-1.8420.28951270.25121644X-RAY DIFFRACTION100
1.842-1.88810.25491530.20531618X-RAY DIFFRACTION100
1.8881-1.93910.20451490.1861631X-RAY DIFFRACTION100
1.9391-1.99620.21271410.17311620X-RAY DIFFRACTION100
1.9962-2.06060.18711460.16211623X-RAY DIFFRACTION100
2.0606-2.13420.2251220.16731681X-RAY DIFFRACTION100
2.1342-2.21960.20371250.17011653X-RAY DIFFRACTION100
2.2196-2.32060.20251250.1691658X-RAY DIFFRACTION100
2.3206-2.44290.19961310.16031629X-RAY DIFFRACTION100
2.4429-2.59590.19671660.17311624X-RAY DIFFRACTION100
2.5959-2.79630.18631390.16971658X-RAY DIFFRACTION100
2.7963-3.07750.20681360.1671655X-RAY DIFFRACTION100
3.0775-3.52240.22181230.16491685X-RAY DIFFRACTION100
3.5224-4.4360.1791180.15411711X-RAY DIFFRACTION100
4.436-100.1961500.17361715X-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)
12.84480.1061-0.98192.8736-0.0011.72520.0506-0.1722-0.28250.08020.18531.07270.2265-0.4222-0.08120.1877-0.01810.06450.27230.10460.457922.5315-28.4775-9.2098
25.09694.2467-1.0384.1889-1.10662.79760.1646-0.62531.33010.813-0.01820.6481-0.3042-0.2559-0.27080.47860.08260.11840.2738-0.04170.292133.4971-9.72661.0915
35.44340.964-2.59385.1026-0.96785.3626-0.17280.77770.8865-0.2530.2263-0.784-0.40320.50310.31510.3136-0.0713-0.01560.43720.08080.366951.8129-9.2916-12.2712
45.5675-0.13551.05253.12270.81022.2574-0.07110.12070.38750.3778-0.1638-0.4439-0.05320.25720.17690.3102-0.0005-0.07810.1610.02530.23946.2681-13.8263-5.031
51.9272-1.04430.2742.5721-0.38761.74340.0184-0.1666-0.31540.52480.06150.37170.0803-0.27260.00790.2564-0.01510.06680.23980.0590.214433.9276-28.4495-3.0914
62.59271.0108-0.4535.1885-1.04862.0562-0.07340.20830.1159-0.16720.03230.1943-0.1014-0.16070.03490.1602-0.0004-0.01270.15210.02590.121636.908-17.9891-14.9608
72.2261-2.2012-2.63254.35225.3276.66140.20871.0413-0.2131-1.3583-0.3350.80550.5311-0.38070.21350.539-0.0221-0.11960.3953-0.01140.2631.2123-22.2485-24.5769
83.0978-0.137-0.48036.2345-0.12342.1017-0.09590.236-0.0479-0.36460.08260.4986-0.0285-0.2190.04550.1758-0.0104-0.040.17790.03640.117133.3368-20.0924-16.071
92.1903-3.55980.69925.7854-0.9140.48250.09980.1065-0.1361-0.0954-0.1232-0.04260.07440.0489-0.02630.2233-0.01180.01960.17460.01870.213341.8268-30.8172-8.436
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 188 through 215 )
2X-RAY DIFFRACTION2chain 'A' and (resid 216 through 231 )
3X-RAY DIFFRACTION3chain 'A' and (resid 232 through 246 )
4X-RAY DIFFRACTION4chain 'A' and (resid 247 through 266 )
5X-RAY DIFFRACTION5chain 'A' and (resid 267 through 303 )
6X-RAY DIFFRACTION6chain 'A' and (resid 304 through 342 )
7X-RAY DIFFRACTION7chain 'A' and (resid 343 through 356 )
8X-RAY DIFFRACTION8chain 'A' and (resid 357 through 382 )
9X-RAY DIFFRACTION9chain 'A' and (resid 383 through 402 )

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