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- PDB-6s4a: Structure of human MTHFD2 in complex with TH9028 -

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Basic information

Entry
Database: PDB / ID: 6s4a
TitleStructure of human MTHFD2 in complex with TH9028
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
Chem-KUK / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / PHOSPHATE ION / Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsGustafsson, R. / Scaletti, E.R. / Bonagas, N. / Gustafsson, N.M. / Henriksson, M. / Abdurakhmanov, E. / Andersson, Y. / Bengtsson, C. / Borhade, S. / Desroses, M. ...Gustafsson, R. / Scaletti, E.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: Database references / Refinement description
Category: citation / citation_author ...citation / citation_author / database_2 / refine
Item: _citation.country / _citation.journal_abbrev ..._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 / _refine.pdbx_diffrn_id
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)72,27019
Polymers68,6292
Non-polymers3,64117
Water4,125229
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8640 Å2
ΔGint-137 kcal/mol
Surface area22880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.068, 115.068, 113.549
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, 246 molecules

#2: Chemical ChemComp-KUK / (2~{S})-2-[[5-[[2,4-bis(azanyl)-6-oxidanylidene-5~{H}-pyrimidin-5-yl]carbamoylamino]pyridin-2-yl]carbonylamino]-4-(1~{H}-1,2,3,4-tetrazol-5-yl)butanoic acid / TH9028


Mass: 458.392 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18N12O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#5: Chemical
ChemComp-MPD / (4S)-2-METHYL-2,4-PENTANEDIOL


Mass: 118.174 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C6H14O2 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 229 / 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: 3.16 Å3/Da / Density % sol: 61.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES pH 7.8, 80 % v/v MPD

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→49.3 Å / Num. obs: 62083 / % possible obs: 99.9 % / Redundancy: 10.2 % / Net I/σ(I): 13.5
Reflection shellResolution: 1.95→2 Å / Num. unique obs: 4342

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→113.55 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.965 / SU B: 4.283 / SU ML: 0.112 / Cross valid method: THROUGHOUT / ESU R: 0.12 / ESU R Free: 0.122 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21138 3073 5 %RANDOM
Rwork0.16811 ---
obs0.17013 58965 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 58.736 Å2
Baniso -1Baniso -2Baniso -3
1-1.74 Å20.87 Å20 Å2
2--1.74 Å20 Å2
3----5.65 Å2
Refinement stepCycle: 1 / Resolution: 1.95→113.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4483 0 240 229 4952
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0194866
X-RAY DIFFRACTIONr_bond_other_d0.0020.024723
X-RAY DIFFRACTIONr_angle_refined_deg1.8092.0296630
X-RAY DIFFRACTIONr_angle_other_deg1310929
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0825595
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.0824.889180
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.67715828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0311528
X-RAY DIFFRACTIONr_chiral_restr0.0940.2780
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0215180
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02848
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_it3.8185.4862380
X-RAY DIFFRACTIONr_mcbond_other3.8165.4852379
X-RAY DIFFRACTIONr_mcangle_it5.1068.1952975
X-RAY DIFFRACTIONr_mcangle_other5.1058.1962976
X-RAY DIFFRACTIONr_scbond_it5.7716.3312486
X-RAY DIFFRACTIONr_scbond_other5.776.3342487
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other8.2229.2933656
X-RAY DIFFRACTIONr_long_range_B_refined10.19467.5065332
X-RAY DIFFRACTIONr_long_range_B_other10.19467.5265333
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.95→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 247 -
Rwork0.366 4297 -
obs--99.76 %

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