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- PDB-6yw2: HIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with bicyclic F... -

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Basic information

Entry
Database: PDB / ID: 6yw2
TitleHIF prolyl hydroxylase 2 (PHD2/ EGLN1) in complex with bicyclic FG2216 and RaPID-derived cyclic peptide 3C (14-mer)
Components
  • Egl nine homolog 1
  • PHD2-SPECIFIC RaPID CYCLIC PEPTIDE 3C (14-MER)
KeywordsOXIDOREDUCTASE / NON-HEME DIOXYGENASE / IRON / 2-OXOGLUTARATE / HYPOXIA-INDUCIBLE FACTOR / HIF / HIF PROLYL HYDROXYLASE DOMAIN 2 / PHD2 / EGLN1 / OXYGENASE / HYPOXIA / DNA-BINDING / METAL-BINDING / TRANSCRIPTION / HELIX-LOOP-HELIX-BETA / DSBH / FACIAL TRIAD / CYTOPLASM / TRANSCRIPTION/EPIGENETIC REGULATION / SIGNALING / DEVELOPMENT / CELL STRUCTURE / BETA-HYDROXYLATION / TRANSCRIPTION ACTIVATOR/INHIBITOR / UBL CONJUGATION / POLYMORPHISM / VITAMIN C / ZINC-FINGER / FAMILIAL ERYTHROCYTOSIS / BREAST CANCER / TRANSCRIPTION COMPLEX
Function / homology
Function and homology information


peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / negative regulation of hypoxia-inducible factor-1alpha signaling pathway / peptidyl-proline dioxygenase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / regulation of modification of postsynaptic structure / labyrinthine layer development / 2-oxoglutarate-dependent dioxygenase activity ...peptidyl-proline 4-dioxygenase activity / hypoxia-inducible factor-proline dioxygenase activity / hypoxia-inducible factor-proline dioxygenase / negative regulation of hypoxia-inducible factor-1alpha signaling pathway / peptidyl-proline dioxygenase activity / regulation protein catabolic process at postsynapse / intracellular oxygen homeostasis / regulation of modification of postsynaptic structure / labyrinthine layer development / 2-oxoglutarate-dependent dioxygenase activity / heart trabecula formation / cardiac muscle tissue morphogenesis / L-ascorbic acid binding / response to nitric oxide / ventricular septum morphogenesis / enzyme inhibitor activity / regulation of angiogenesis / regulation of neuron apoptotic process / ferrous iron binding / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / cellular response to hypoxia / intracellular iron ion homeostasis / response to hypoxia / postsynaptic density / intracellular membrane-bounded organelle / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleus / cytoplasm / cytosol
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 signature. / Zinc finger, MYND-type / Zinc finger MYND-type profile. / Oxoglutarate/iron-dependent dioxygenase / Fe(2+) 2-oxoglutarate dioxygenase domain profile.
Similarity search - Domain/homology
: / Chem-UN9 / Egl nine homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.14 Å
AuthorsChowdhury, R. / Schofield, C.J.
Citation
Journal: Sci Rep / Year: 2020
Title: Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2.
Authors: Chowdhury, R. / Abboud, M.I. / McAllister, T.E. / Banerji, B. / Bhushan, B. / Sorensen, J.L. / Kawamura, A. / Schofield, C.J.
#1: Journal: Nat Commun / Year: 2016
Title: Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.
Authors: Chowdhury, R. / Leung, I.K. / Tian, Y.M. / Abboud, M.I. / Ge, W. / Domene, C. / Cantrelle, F.X. / Landrieu, I. / Hardy, A.P. / Pugh, C.W. / Ratcliffe, P.J. / Claridge, T.D. / Schofield, C.J.
History
DepositionApr 29, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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: Egl nine homolog 1
B: PHD2-SPECIFIC RaPID CYCLIC PEPTIDE 3C (14-MER)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,1734
Polymers27,8382
Non-polymers3362
Water1,76598
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2240 Å2
ΔGint-27 kcal/mol
Surface area10490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.181, 46.181, 202.262
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65

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Components

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


Mass: 26036.582 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: CATALYTIC DOMAIN (aa 181-407) / Source: (gene. exp.) Homo sapiens (human) / Gene: EGLN1, C1orf12, PNAS-118, PNAS-137 / Plasmid: PET28A(+) / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9GZT9, hypoxia-inducible factor-proline dioxygenase
#2: Protein/peptide PHD2-SPECIFIC RaPID CYCLIC PEPTIDE 3C (14-MER)


Mass: 1801.050 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#3: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mn
#4: Chemical ChemComp-UN9 / N-[(1-CHLORO-4-HYDROXYISOQUINOLIN-3-YL)CARBONYL]GLYCINE


Mass: 280.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H9ClN2O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 98 / 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: 2.5 Å3/Da / Density % sol: 50.82 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: Sample: 1.0 mM PHD2, 1.5 mM MnCl2, 2.0 mM compound, 1.0 mM 3C; Reservoir: 22% w/v polyethylene glycol 3350, 0.25 M magnesium formate, 2 mM MnCl2; Sitting drop (2 ul), protein-to-well ratio, 1:1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 30, 2017 / Details: MIRRORS
RadiationMonochromator: SI 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.14→39.994 Å / Num. obs: 13502 / % possible obs: 100 % / Redundancy: 15.4 % / Biso Wilson estimate: 34.7 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.044 / Rrim(I) all: 0.174 / Rsym value: 0.168 / Net I/av σ(I): 4.3 / Net I/σ(I): 12.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allRsym value% possible all
2.14-2.2615.81.3412.1719620.7230.3491.3861.341100
2.26-2.3915.30.9780.818560.2591.0120.978100
2.39-2.5615.40.784117650.2070.8110.784100
2.56-2.7615.40.5521.416080.1460.5710.552100
2.76-3.0315.90.3192.414940.0830.330.319100
3.03-3.3815.30.1774.213460.0470.1840.177100
3.38-3.9115.20.1126.512090.030.1160.112100
3.91-4.7915.40.079.910050.0190.0720.07100
4.79-6.7714.50.06410.58040.0170.0660.064100
6.77-101.13114.70.04315.54530.0110.0440.04399.9

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L9R

5l9r


Resolution: 2.14→37.191 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 23.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1962 626 4.67 %
Rwork0.1701 --
obs0.1714 13419 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT MODEL / Bsol: 48.8 Å2 / ksol: 0.41 e/Å3
Displacement parametersBiso max: 117.42 Å2 / Biso mean: 46.3511 Å2 / Biso min: 24.84 Å2
Refinement stepCycle: final / Resolution: 2.14→37.191 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1735 0 28 98 1861
Biso mean--35.63 44.38 -
Num. residues----223
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONf_bond_d0.0050.0551805
X-RAY DIFFRACTIONf_angle_d1.0478.4062447
X-RAY DIFFRACTIONf_dihedral_angle_d5.15682.1761038
X-RAY DIFFRACTIONf_chiral_restr0.0480.163258
X-RAY DIFFRACTIONf_plane_restr0.0040.029314
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.1402-2.21670.2838690.24541293
2.2167-2.30540.2532500.2331307
2.3054-2.41040.2937710.21741242
2.4104-2.53740.1951590.21091273
2.5374-2.69630.2314480.20371285
2.6963-2.90440.2271680.20231283
2.9044-3.19660.2298630.17661276
3.1966-3.65880.1901560.14971276
3.6588-4.60830.1689730.13291286
4.6083-37.1910.1555690.14951272
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)
13.51210.148-0.2793.8969-0.16482.71290.0070.05910.42070.1161-0.13910.1217-0.5253-0.3911-0.04870.39460.0347-0.01560.32820.03160.351-2.334461.6934.0467
22.3025-0.8820.62782.271-0.42431.8963-0.03310.34370.2606-0.189-0.0169-0.0717-0.0927-0.045-0.04390.30930.02490.02610.41330.02210.35912.438154.5715-0.0526
33.05330.3550.20713.7137-0.23254.03150.04290.47930.0591-0.770.3411-0.62680.18670.6264-0.25550.3672-0.05720.06590.6773-0.06520.634621.225747.30520.1248
44.8915-2.27351.66323.4415-0.15255.72880.1041-0.1301-0.87930.67840.4219-0.72790.55160.5053-0.53120.34780.0815-0.07970.5427-0.02580.612117.830541.63210.775
53.3614-0.86830.16112.6604-1.11183.78780.1566-0.51240.58580.291-0.1045-0.7425-0.55090.4114-0.04720.4264-0.1121-0.02570.4423-0.04020.448711.371958.39299.1981
63.8154-1.57392.12772.405-1.47825.0157-0.0854-0.57010.19660.13660.0981-0.0166-0.891-0.3674-0.01150.48760.00750.00070.4658-0.00160.4794-2.446158.947417.0511
70.5837-0.52540.45341.79971.1732.14480.0824-0.0476-0.04750.3130.0407-0.40460.35060.2742-0.07290.28480.016-0.01120.3969-0.02170.389312.01341.9568.3503
81.6656-0.9874-2.54862.54711.12983.9296-0.3289-0.1982-0.23140.28390.07250.38730.23710.36260.28420.2821-0.0442-0.02160.33660.04610.3610.162437.610411.8265
90.1638-0.6234-0.31524.54771.67580.6353-0.0420.0335-0.1446-0.4537-0.0124-0.2439-0.38060.0105-0.03150.2753-0.0091-0.02920.3958-0.00820.30827.315446.83482.1115
103.3433-0.5860.20311.64411.08833.58720.17660.4678-0.7269-0.2004-0.4030.3007-0.143-0.78240.17750.3446-0.0109-0.0630.4186-0.06820.3851-2.639240.153-1.7227
112.69382.0965-0.57833.1330.2483.786-0.04741.78510.6692-0.40320.19260.27590.2569-0.6474-0.12840.4150.0267-0.04940.4255-0.01240.31380.535245.2656-3.5185
123.55-0.78750.26731.9041.23092.18360.186-0.1846-0.0838-0.1206-0.0697-0.0129-0.2302-0.1164-0.14760.3030.0156-0.02990.44220.02350.2748-2.051848.39338.4895
132.6815-0.8495-0.87551.22150.50271.7398-0.02710.1593-0.2515-0.14980.1135-0.01560.5016-0.14790.00240.3655-0.0023-0.04760.2825-0.00070.34811.580836.58851.1296
142.1135-1.1205-0.4433.95372.04983.52560.2990.07750.12340.03110.1296-0.5309-0.0787-0.1457-0.39290.26210.0009-0.03430.3186-0.00810.36828.252446.47749.3444
151.00711.00130.4553.594-0.8753.20370.11450.2284-0.00270.00110.01090.3346-0.4899-0.4772-0.1360.4529-0.01420.03110.4756-0.00750.33181.299246.201726.9421
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 188:204)A188 - 204
2X-RAY DIFFRACTION2(chain A and resid 205:215)A205 - 215
3X-RAY DIFFRACTION3(chain A and resid 216:232)A216 - 232
4X-RAY DIFFRACTION4(chain A and resid 233:266)A233 - 266
5X-RAY DIFFRACTION5(chain A and resid 267:283)A267 - 283
6X-RAY DIFFRACTION6(chain A and resid 284:293)A284 - 293
7X-RAY DIFFRACTION7(chain A and resid 294:306)A294 - 306
8X-RAY DIFFRACTION8(chain A and resid 307:320)A307 - 320
9X-RAY DIFFRACTION9(chain A and resid 321:335)A321 - 335
10X-RAY DIFFRACTION10(chain A and resid 336:350)A336 - 350
11X-RAY DIFFRACTION11(chain A and resid 351:361)A351 - 361
12X-RAY DIFFRACTION12(chain A and resid 362:371)A362 - 371
13X-RAY DIFFRACTION13(chain A and resid 372:381)A372 - 381
14X-RAY DIFFRACTION14(chain A and resid 382:392)A382 - 392
15X-RAY DIFFRACTION15(chain A and resid 393:403)A393 - 403

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