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- PDB-6s4f: Structure of human MTHFD2 in complex with TH9619 -

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Basic information

Entry
Database: PDB / ID: 6s4f
TitleStructure of human MTHFD2 in complex with TH9619
ComponentsBifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
KeywordsOXIDOREDUCTASE
Function / homology
Function and homology information


methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity / methylenetetrahydrofolate dehydrogenase (NADP+) activity / Metabolism of folate and pterines / tetrahydrofolate metabolic process / tetrahydrofolate interconversion / phosphate ion binding / folic acid metabolic process ...methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity / methylenetetrahydrofolate dehydrogenase (NADP+) activity / Metabolism of folate and pterines / tetrahydrofolate metabolic process / tetrahydrofolate interconversion / phosphate ion binding / folic acid metabolic process / mitochondrial matrix / magnesium ion binding / mitochondrion / extracellular space
Similarity search - Function
Tetrahydrofolate dehydrogenase/cyclohydrolase signature 1. / Tetrahydrofolate dehydrogenase/cyclohydrolase signature 2. / Tetrahydrofolate dehydrogenase/cyclohydrolase, conserved site / Tetrahydrofolate dehydrogenase/cyclohydrolase / Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain / Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain / Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain / Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain / Aminoacid dehydrogenase-like, N-terminal domain superfamily / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Chem-KUN / PHOSPHATE ION / Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsScaletti, E.R. / Gustafsson, R. / Bonagas, N. / Gustafsson, N.M. / Henriksson, M. / Abdurakhmanov, E. / Andersson, Y. / Bengtsson, C. / Borhade, S. / Desroses, M. ...Scaletti, E.R. / Gustafsson, R. / Bonagas, N. / Gustafsson, N.M. / Henriksson, M. / Abdurakhmanov, E. / Andersson, Y. / Bengtsson, C. / Borhade, S. / Desroses, M. / Farnegardh, K. / Garg, N. / Gokturk, C. / Haraldsson, M. / Iliev, P. / Jarvius, M. / Jemth, A.S. / Kalderen, C. / Karsten, S. / Klingegard, F. / Koolmeister, T. / Martens, U. / Llona-Minguez, S. / Loseva, O. / Marttila, P. / Michel, M. / Moulson, R. / Nordstrom, H. / Paulin, C. / Pham, T. / Pudelko, L. / Rasti, A. / Roos, A.K. / Sarno, A. / Sandberg, L. / Scobie, M. / Sjoberg, B. / Svensson, R. / Unterlass, J.E. / Vallin, K. / Vo, D. / Wiita, E. / Warpman-Berglund, U. / Homan, E.J. / Helleday, T. / Stenmark, P.
CitationJournal: Nat Cancer / Year: 2022
Title: Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.
Authors: Bonagas, N. / Gustafsson, N.M.S. / Henriksson, M. / Marttila, P. / Gustafsson, R. / Wiita, E. / Borhade, S. / Green, A.C. / Vallin, K.S.A. / Sarno, A. / Svensson, R. / Gokturk, C. / Pham, T. ...Authors: Bonagas, N. / Gustafsson, N.M.S. / Henriksson, M. / Marttila, P. / Gustafsson, R. / Wiita, E. / Borhade, S. / Green, A.C. / Vallin, K.S.A. / Sarno, A. / Svensson, R. / Gokturk, C. / Pham, T. / Jemth, A.S. / Loseva, O. / Cookson, V. / Kiweler, N. / Sandberg, L. / Rasti, A. / Unterlass, J.E. / Haraldsson, M. / Andersson, Y. / Scaletti, E.R. / Bengtsson, C. / Paulin, C.B.J. / Sanjiv, K. / Abdurakhmanov, E. / Pudelko, L. / Kunz, B. / Desroses, M. / Iliev, P. / Farnegardh, K. / Kramer, A. / Garg, N. / Michel, M. / Haggblad, S. / Jarvius, M. / Kalderen, C. / Jensen, A.B. / Almlof, I. / Karsten, S. / Zhang, S.M. / Haggblad, M. / Eriksson, A. / Liu, J. / Glinghammar, B. / Nekhotiaeva, N. / Klingegard, F. / Koolmeister, T. / Martens, U. / Llona-Minguez, S. / Moulson, R. / Nordstrom, H. / Parrow, V. / Dahllund, L. / Sjoberg, B. / Vargas, I.L. / Vo, D.D. / Wannberg, J. / Knapp, S. / Krokan, H.E. / Arvidsson, P.I. / Scobie, M. / Meiser, J. / Stenmark, P. / Berglund, U.W. / Homan, E.J. / Helleday, T.
History
DepositionJun 27, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / database_2 / database_PDB_caveat / entity / pdbx_entity_nonpoly / pdbx_validate_chiral
Item: _chem_comp.name / _citation.country ..._chem_comp.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.0Apr 12, 2023Group: Non-polymer description / Structure summary / Category: chem_comp / entity
Item: _chem_comp.formula / _chem_comp.formula_weight / _entity.formula_weight
Revision 2.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
B: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,90315
Polymers68,6292
Non-polymers2,27413
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6220 Å2
ΔGint-82 kcal/mol
Surface area22750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.895, 116.895, 112.965
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial


Mass: 34314.746 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTHFD2, NMDMC / Production host: Escherichia coli (E. coli)
References: UniProt: P13995, methylenetetrahydrofolate dehydrogenase (NAD+), methenyltetrahydrofolate cyclohydrolase

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Non-polymers , 5 types, 175 molecules

#2: Chemical ChemComp-KUN / (E,4S)-4-[[5-[2-[2,6-bis(azanyl)-4-oxidanylidene-1H-pyrimidin-5-yl]ethanoylamino]-3-fluoranyl-pyridin-2-yl]carbonylamino]pent-2-enedioic acid / TH9619


Mass: 451.366 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18FN7O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.25 Å3/Da / Density % sol: 62.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES pH 7.6, 75 % v/v MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 1.09 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.09 Å / Relative weight: 1
ReflectionResolution: 2.2→75.4 Å / Num. obs: 44494 / % possible obs: 100 % / Redundancy: 20.3 % / Net I/σ(I): 13.9
Reflection shellResolution: 2.2→2.27 Å / Num. unique obs: 3820

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→75.4 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.955 / SU B: 7.267 / SU ML: 0.165 / Cross valid method: THROUGHOUT / ESU R: 0.186 / ESU R Free: 0.169 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22534 2131 4.8 %RANDOM
Rwork0.18395 ---
obs0.18597 42267 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 68.411 Å2
Baniso -1Baniso -2Baniso -3
1-2.12 Å21.06 Å20 Å2
2--2.12 Å20 Å2
3----6.88 Å2
Refinement stepCycle: 1 / Resolution: 2.2→75.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4444 0 143 162 4749
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194654
X-RAY DIFFRACTIONr_bond_other_d0.0020.024479
X-RAY DIFFRACTIONr_angle_refined_deg1.7021.9926326
X-RAY DIFFRACTIONr_angle_other_deg1.0342.99710393
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5565584
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.83924.971175
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.78615805
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3911526
X-RAY DIFFRACTIONr_chiral_restr0.0980.2741
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0215031
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02802
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it4.8596.592343
X-RAY DIFFRACTIONr_mcbond_other4.8556.5882342
X-RAY DIFFRACTIONr_mcangle_it6.5869.8722923
X-RAY DIFFRACTIONr_mcangle_other6.5859.8742924
X-RAY DIFFRACTIONr_scbond_it6.1257.2482311
X-RAY DIFFRACTIONr_scbond_other6.1247.2482311
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.88510.6443404
X-RAY DIFFRACTIONr_long_range_B_refined11.37381.5475227
X-RAY DIFFRACTIONr_long_range_B_other11.37481.5455227
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 151 -
Rwork0.354 3129 -
obs--99.79 %

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