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- PDB-9isc: Human MTHFD2 in complex with compound 16a -

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Basic information

Entry
Database: PDB / ID: 9isc
TitleHuman MTHFD2 in complex with compound 16a
ComponentsBifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
KeywordsOXIDOREDUCTASE / MTHFD2 / methylenetetrahydrofolate dehydrogenase 2 / 1C metabolism / mitochondria / OSIDOREDUCTASE
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
: / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / PHOSPHATE ION / Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsLee, L.C. / Wu, S.Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization.
Authors: Chang, H.H. / Lee, L.C. / Hsu, T. / Peng, Y.H. / Huang, C.H. / Yeh, T.K. / Lu, C.T. / Huang, Z.T. / Hsueh, C.C. / Kung, F.C. / Lin, L.M. / Huang, Y.C. / Wang, Y.H. / Li, L.H. / Tang, Y.C. / ...Authors: Chang, H.H. / Lee, L.C. / Hsu, T. / Peng, Y.H. / Huang, C.H. / Yeh, T.K. / Lu, C.T. / Huang, Z.T. / Hsueh, C.C. / Kung, F.C. / Lin, L.M. / Huang, Y.C. / Wang, Y.H. / Li, L.H. / Tang, Y.C. / Chang, L. / Hsieh, C.C. / Jiaang, W.T. / Kuo, C.C. / Wu, S.Y.
History
DepositionJul 17, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 1, 2025Provider: repository / Type: Initial release

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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)71,6268
Polymers69,1942
Non-polymers2,4326
Water1,44180
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6010 Å2
ΔGint-51 kcal/mol
Surface area22190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.559, 115.559, 112.958
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial


Mass: 34597.020 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 BL21(DE3) (bacteria)
References: UniProt: P13995, methylenetetrahydrofolate dehydrogenase (NAD+), methenyltetrahydrofolate cyclohydrolase
#2: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical ChemComp-A1L22 / (2~{S})-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1~{H}-pyrimidin-5-yl]carbamoylamino]phenyl]carbonylamino]-4-(1~{H}-1,2,3,4-tetrazol-5-yl)butanoic acid


Mass: 457.403 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19N11O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 3.15 Å3/Da / Density % sol: 60.91 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / Details: isopropanol, Bis-Tris pH 7.1, PEG 400, PEG 1000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL15A1 / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Mar 21, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→30 Å / Num. obs: 27738 / % possible obs: 98 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 12.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.54-2.632.90.37628230.8250.9510.2590.461.05399.8
2.63-2.742.90.33228260.8550.960.2280.4061.07899.8
2.74-2.862.90.23627830.9380.9840.1590.2871.08599.6
2.86-3.012.90.17427850.9630.990.1160.2111.05199.4
3.01-3.22.90.13628110.9720.9930.0910.1651.06799
3.2-3.452.90.08627830.9890.9970.0570.1041.03298.6
3.45-3.792.90.0627700.9930.9980.040.0721.01898.1
3.79-4.342.90.04727490.9960.9990.0310.0561.00496.8
4.34-5.462.90.03227300.9980.9990.0210.0391.05196.1
5.46-3030.02126780.99910.0140.0251.02592.6

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
SCALEPACKdata scaling
HKL-20002.3.10data reduction
MOLREP11phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.54→27.18 Å / SU ML: 0.36 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2397 1364 4.93 %
Rwork0.1919 --
obs0.1942 27684 97.9 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.54→27.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4389 0 164 80 4633
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.037
X-RAY DIFFRACTIONf_dihedral_angle_d22.1611790
X-RAY DIFFRACTIONf_chiral_restr0.057742
X-RAY DIFFRACTIONf_plane_restr0.01801
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.54-2.630.32551470.26262674X-RAY DIFFRACTION100
2.63-2.740.35711290.25872687X-RAY DIFFRACTION100
2.74-2.860.32611250.25112651X-RAY DIFFRACTION99
2.86-3.010.32161530.22532623X-RAY DIFFRACTION99
3.01-3.20.32311340.24022670X-RAY DIFFRACTION99
3.2-3.450.24671650.20042622X-RAY DIFFRACTION99
3.45-3.790.2111390.18952624X-RAY DIFFRACTION98
3.79-4.340.23651250.16822618X-RAY DIFFRACTION97
4.34-5.460.18651310.15932598X-RAY DIFFRACTION96
5.46-27.180.16781160.15722553X-RAY DIFFRACTION93

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