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- PDB-6plf: Crystal structure of human PHGDH complexed with Compound 1 -

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Basic information

Entry
Database: PDB / ID: 6plf
TitleCrystal structure of human PHGDH complexed with Compound 1
ComponentsD-3-phosphoglycerate dehydrogenase
KeywordsOXIDOREDUCTASE/INHIBITOR / DEHYDROGENASE / SERINE METABOLISM / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


gamma-aminobutyric acid metabolic process / threonine metabolic process / 2-oxoglutarate reductase / glial cell development / phosphoglycerate dehydrogenase / phosphoglycerate dehydrogenase activity / taurine metabolic process / Serine biosynthesis / glycine metabolic process / malate dehydrogenase ...gamma-aminobutyric acid metabolic process / threonine metabolic process / 2-oxoglutarate reductase / glial cell development / phosphoglycerate dehydrogenase / phosphoglycerate dehydrogenase activity / taurine metabolic process / Serine biosynthesis / glycine metabolic process / malate dehydrogenase / L-serine biosynthetic process / L-malate dehydrogenase activity / neural tube development / G1 to G0 transition / spinal cord development / glutamine metabolic process / brain development / neuron projection development / NAD binding / regulation of gene expression / electron transfer activity / extracellular exosome / cytosol
Similarity search - Function
D-3-phosphoglycerate dehydrogenase / D-3-phosphoglycerate dehydrogenase, ASB domain / D-3-phosphoglycerate dehydrogenase intervening domain / Allosteric substrate binding domain superfamily / D-isomer specific 2-hydroxyacid dehydrogenases signature 2. / D-isomer specific 2-hydroxyacid dehydrogenases NAD-binding signature. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site 1 / D-isomer specific 2-hydroxyacid dehydrogenases signature 3. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site / D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain ...D-3-phosphoglycerate dehydrogenase / D-3-phosphoglycerate dehydrogenase, ASB domain / D-3-phosphoglycerate dehydrogenase intervening domain / Allosteric substrate binding domain superfamily / D-isomer specific 2-hydroxyacid dehydrogenases signature 2. / D-isomer specific 2-hydroxyacid dehydrogenases NAD-binding signature. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site 1 / D-isomer specific 2-hydroxyacid dehydrogenases signature 3. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site / D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain / D-isomer specific 2-hydroxyacid dehydrogenase, catalytic domain / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain / D-isomer specific 2-hydroxyacid dehydrogenase, NAD binding domain / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-ONV / D-3-phosphoglycerate dehydrogenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsOlland, A. / Lakshminarasimhan, D. / White, A. / Suto, R.K.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.
Authors: Mullarky, E. / Xu, J. / Robin, A.D. / Huggins, D.J. / Jennings, A. / Noguchi, N. / Olland, A. / Lakshminarasimhan, D. / Miller, M. / Tomita, D. / Michino, M. / Su, T. / Zhang, G. / Stamford, ...Authors: Mullarky, E. / Xu, J. / Robin, A.D. / Huggins, D.J. / Jennings, A. / Noguchi, N. / Olland, A. / Lakshminarasimhan, D. / Miller, M. / Tomita, D. / Michino, M. / Su, T. / Zhang, G. / Stamford, A.W. / Meinke, P.T. / Kargman, S. / Cantley, L.C.
History
DepositionJun 30, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 7, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 4, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: D-3-phosphoglycerate dehydrogenase
B: D-3-phosphoglycerate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,5209
Polymers67,2622
Non-polymers1,2587
Water5,098283
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6040 Å2
ΔGint-9 kcal/mol
Surface area24650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.202, 126.192, 59.504
Angle α, β, γ (deg.)90.000, 99.760, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein D-3-phosphoglycerate dehydrogenase / 3-PGDH / 2-oxoglutarate reductase / Malate dehydrogenase


Mass: 33630.762 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHGDH, PGDH3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: O43175, phosphoglycerate dehydrogenase, 2-oxoglutarate reductase, malate dehydrogenase
#2: Chemical ChemComp-ONV / 4-{(1S)-1-[(5-chloro-6-{[(5S)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1H-indole-2-carbonyl)amino]-2-hydroxyethyl}benzoic acid


Mass: 473.863 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20ClN3O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


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


Mass: 18.015 Da / Num. of mol.: 283 / 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: 2.38 Å3/Da / Density % sol: 48.28 %
Crystal growTemperature: 297 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1 M Bis-Tris pH 5.5 and a range of PEG 3350 (24% to 29%), using micro-seeding

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.07822 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 11, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07822 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 66230 / % possible obs: 96 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.06 / Rpim(I) all: 0.039 / Rrim(I) all: 0.072 / Χ2: 1.004 / Net I/σ(I): 14.6 / Num. measured all: 209488
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.7-1.762.90.56865380.7660.390.6921.00595
1.76-1.8330.45366010.8450.3070.5491.01596.1
1.83-1.912.80.30363110.9040.2160.3741.00691.4
1.91-2.0230.21764760.9510.1490.2651.01994.4
2.02-2.143.40.15167990.9770.0970.181.01698.6
2.14-2.313.40.1167920.9860.0710.132198.7
2.31-2.543.40.07968290.9920.0510.0941.0199
2.54-2.913.30.0667710.9950.0390.072198.1
2.91-3.662.90.04362280.9960.030.0520.9990.2
3.66-503.50.0468850.9960.0250.0480.98398.4

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→40.37 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.944 / SU B: 2.989 / SU ML: 0.092 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.107 / ESU R Free: 0.108
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2233 3288 5 %RANDOM
Rwork0.1845 ---
obs0.1864 62907 95.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 141.11 Å2 / Biso mean: 40.486 Å2 / Biso min: 15.32 Å2
Baniso -1Baniso -2Baniso -3
1--1.92 Å20 Å2-0.19 Å2
2--4.22 Å2-0 Å2
3----2.11 Å2
Refinement stepCycle: final / Resolution: 1.7→40.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4349 0 86 283 4718
Biso mean--39.49 40.26 -
Num. residues----597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0134586
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174332
X-RAY DIFFRACTIONr_angle_refined_deg1.71.666221
X-RAY DIFFRACTIONr_angle_other_deg1.3991.58410031
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.3935617
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.52822.293205
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.17515773
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8591533
X-RAY DIFFRACTIONr_chiral_restr0.0860.2627
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0235231
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02882
LS refinement shellResolution: 1.698→1.742 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.322 230 -
Rwork0.303 4508 -
all-4738 -
obs--92.45 %

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