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- PDB-6rih: Crystal structure of PHGDH in complex with compound 9 -

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Basic information

Entry
Database: PDB / ID: 6rih
TitleCrystal structure of PHGDH in complex with compound 9
ComponentsD-3-phosphoglycerate dehydrogenase
KeywordsOXIDOREDUCTASE / Protein-Ligand complex / Dehydrogenase
Function / homology
Function and homology information


threonine metabolic process / 2-oxoglutarate reductase / gamma-aminobutyric acid metabolic process / glial cell development / phosphoglycerate dehydrogenase / phosphoglycerate dehydrogenase activity / taurine metabolic process / Serine biosynthesis / glycine metabolic process / L-serine biosynthetic process ...threonine metabolic process / 2-oxoglutarate reductase / gamma-aminobutyric acid metabolic process / glial cell development / phosphoglycerate dehydrogenase / phosphoglycerate dehydrogenase activity / taurine metabolic process / Serine biosynthesis / glycine metabolic process / L-serine biosynthetic process / malate dehydrogenase / L-malate dehydrogenase (NAD+) activity / neural tube development / spinal cord development / G1 to G0 transition / glutamine metabolic process / brain development / NAD binding / neuron projection development / 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 dehydrogenases signature 3. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site 1 / 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 dehydrogenases signature 3. / D-isomer specific 2-hydroxyacid dehydrogenase, NAD-binding domain conserved site 1 / 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-K4T / D-3-phosphoglycerate dehydrogenase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsBader, G. / Wolkerstorfer, B. / Zoephel, A.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) InhibitorBI-4924Disrupts Serine Biosynthesis.
Authors: Weinstabl, H. / Treu, M. / Rinnenthal, J. / Zahn, S.K. / Ettmayer, P. / Bader, G. / Dahmann, G. / Kessler, D. / Rumpel, K. / Mischerikow, N. / Savarese, F. / Gerstberger, T. / Mayer, M. / ...Authors: Weinstabl, H. / Treu, M. / Rinnenthal, J. / Zahn, S.K. / Ettmayer, P. / Bader, G. / Dahmann, G. / Kessler, D. / Rumpel, K. / Mischerikow, N. / Savarese, F. / Gerstberger, T. / Mayer, M. / Zoephel, A. / Schnitzer, R. / Sommergruber, W. / Martinelli, P. / Arnhof, H. / Peric-Simov, B. / Hofbauer, K.S. / Garavel, G. / Scherbantin, Y. / Mitzner, S. / Fett, T.N. / Scholz, G. / Bruchhaus, J. / Burkard, M. / Kousek, R. / Ciftci, T. / Sharps, B. / Schrenk, A. / Harrer, C. / Haering, D. / Wolkerstorfer, B. / Zhang, X. / Lv, X. / Du, A. / Li, D. / Li, Y. / Quant, J. / Pearson, M. / McConnell, D.B.
History
DepositionApr 24, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 7, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Sep 25, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.3Jan 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: D-3-phosphoglycerate dehydrogenase
B: D-3-phosphoglycerate dehydrogenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8405
Polymers67,2622
Non-polymers5793
Water10,377576
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5410 Å2
ΔGint-46 kcal/mol
Surface area24920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.351, 112.041, 69.116
Angle α, β, γ (deg.)90.000, 96.040, 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 / Fragment: catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PHGDH, PGDH3 / Production host: Escherichia coli (E. coli)
References: UniProt: O43175, phosphoglycerate dehydrogenase, 2-oxoglutarate reductase, malate dehydrogenase
#2: Chemical ChemComp-K4T / ~{N}-cyclopropyl-2-methyl-5-phenyl-pyrazole-3-carboxamide


Mass: 241.288 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H15N3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 576 / 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: 2.55 Å3/Da / Density % sol: 51.79 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.6 / Details: 25 % PEG 8000, 0.1 M MES, 0.2M Lithium sulphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Aug 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→112.04 Å / Num. obs: 35486 / % possible obs: 99.6 % / Redundancy: 4.8 % / Biso Wilson estimate: 29.3 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.038 / Rrim(I) all: 0.084 / Net I/σ(I): 14.5 / Num. measured all: 171723
Reflection shell

Diffraction-ID: 1 / Redundancy: 4.8 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.15-2.630.21177762161020.9790.1070.2376.799.7
3.73-112.040.0413311668940.9980.0210.04728.799.4

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Processing

Software
NameVersionClassification
Aimless0.3.8data scaling
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
TRUNCATEdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2G76

2g76


Resolution: 2.15→40 Å / Cor.coef. Fo:Fc: 0.916 / Cor.coef. Fo:Fc free: 0.867 / SU R Cruickshank DPI: 0.289 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.322 / SU Rfree Blow DPI: 0.237 / SU Rfree Cruickshank DPI: 0.23
RfactorNum. reflection% reflectionSelection details
Rfree0.276 1682 4.89 %RANDOM
Rwork0.222 ---
obs0.225 34428 96.6 %-
Displacement parametersBiso max: 137.41 Å2 / Biso mean: 36.07 Å2 / Biso min: 10.14 Å2
Baniso -1Baniso -2Baniso -3
1-2.5345 Å20 Å2-0.1684 Å2
2---4.6424 Å20 Å2
3---2.1079 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.15→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4474 0 41 576 5091
Biso mean--27.88 34.57 -
Num. residues----598
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1642SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes782HARMONIC5
X-RAY DIFFRACTIONt_it4568HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion615SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5631SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4568HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg6172HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion2.56
X-RAY DIFFRACTIONt_other_torsion18.78
LS refinement shellResolution: 2.15→2.22 Å / Rfactor Rfree error: 0 / Total num. of bins used: 17
RfactorNum. reflection% reflection
Rfree0.457 104 4.48 %
Rwork0.408 2219 -
all0.4103 2323 -
obs--76.38 %
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)
10.257-0.1866-0.3130.59890.38590.63130.0061-0.0042-0.0786-0.0727-0.06750.0944-0.0146-0.03320.0614-0.04820.0117-0.0602-0.1460.00430.28149.2697-0.935266.2665
21.0786-0.2348-0.04110.9877-0.15330.4139-0.0757-0.11150.15920.14470.05110.0083-0.14230.01810.0246-0.05460.025-0.0446-0.1685-0.02270.22692.708123.918787.8811
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A5 - 306
2X-RAY DIFFRACTION2{ B|* }B5 - 306

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