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- PDB-9it6: Human MTHFD2 in complex with compound 16g -

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Basic information

Entry
Database: PDB / ID: 9it6
TitleHuman MTHFD2 in complex with compound 16g
ComponentsBifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
KeywordsOXIDOREDUCTASE / MTHFD2 / methylenetetrahydrofolate dehydrogenase 2 / 1C metabolism / mitochondria
Function / homology
Function and homology information


methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / formate biosynthetic process / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity / methylenetetrahydrofolate dehydrogenase (NADP+) activity / Metabolism of folate and pterines / tetrahydrofolate metabolic process / tetrahydrofolate interconversion / phosphate ion binding ...methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / formate biosynthetic process / 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: 2.04 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 19, 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

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)71,6958
Polymers69,1942
Non-polymers2,5006
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6090 Å2
ΔGint-48 kcal/mol
Surface area21890 Å2
MethodPISA
Unit cell
Length a, b, c (Å)114.849, 114.849, 113.413
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-A1L24 / (2~{S})-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1~{H}-pyrimidin-5-yl]carbamoylamino]-3-chloranyl-phenyl]carbonylamino]-4-(1~{H}-1,2,3,4-tetrazol-5-yl)butanoic acid


Mass: 491.849 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18ClN11O5
#3: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#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.: 188 / 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: 3.12 Å3/Da / Density % sol: 60.58 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop / Details: isopropanol, Bis-Tris pH 7.1, PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL44XU / Wavelength: 0.9 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 2.04→30 Å / Num. obs: 53789 / % possible obs: 99.3 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.062 / Net I/σ(I): 12.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.04-2.114.20.47353690.8180.9480.2520.5411.03399.8
2.11-2.24.30.3353800.9020.9740.1750.3771100
2.2-2.34.20.25553900.9250.980.1370.2931.06599.6
2.3-2.424.30.18654180.9660.9910.0970.2121.007100
2.42-2.574.20.13753940.9820.9960.070.1561.068100
2.57-2.774.20.10553970.9890.9970.0530.1191.0299.9
2.77-3.054.20.0754140.9960.9990.0340.0791.05699.9
3.05-3.494.20.0654090.9960.9990.0280.0671.03999.6
3.49-4.394.10.04853710.9970.9990.0230.0541.09199
4.39-3040.03652470.9980.9990.0180.041.09795.2

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Processing

Software
NameVersionClassification
PHENIX(1.21.1_5286: ???)refinement
SCALEPACKdata scaling
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.04→28.62 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.49 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2237 2783 5.19 %
Rwork0.1965 --
obs0.198 53646 99.04 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.04→28.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4362 0 166 188 4716
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d0.917
X-RAY DIFFRACTIONf_dihedral_angle_d20.5211781
X-RAY DIFFRACTIONf_chiral_restr0.198739
X-RAY DIFFRACTIONf_plane_restr0.008794
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.04-2.070.32931630.29262472X-RAY DIFFRACTION98
2.07-2.110.32751460.26542530X-RAY DIFFRACTION100
2.11-2.150.30961550.25432527X-RAY DIFFRACTION100
2.15-2.190.27261220.24682561X-RAY DIFFRACTION100
2.19-2.240.30231420.24422572X-RAY DIFFRACTION99
2.24-2.290.32971340.27062530X-RAY DIFFRACTION99
2.29-2.350.25971210.22712576X-RAY DIFFRACTION100
2.35-2.420.28281100.22612584X-RAY DIFFRACTION100
2.42-2.490.26831600.21072524X-RAY DIFFRACTION100
2.49-2.570.22911350.21812569X-RAY DIFFRACTION100
2.57-2.660.2661370.20812545X-RAY DIFFRACTION100
2.66-2.760.29391480.22472559X-RAY DIFFRACTION100
2.76-2.890.23661530.21152552X-RAY DIFFRACTION100
2.89-3.040.21251440.20842572X-RAY DIFFRACTION100
3.04-3.230.25541490.21462554X-RAY DIFFRACTION100
3.23-3.480.22661580.19862535X-RAY DIFFRACTION99
3.48-3.830.20811200.18512577X-RAY DIFFRACTION99
3.83-4.380.20571200.16282558X-RAY DIFFRACTION99
4.39-5.520.16891510.15862532X-RAY DIFFRACTION98
5.52-28.620.16091150.17442434X-RAY DIFFRACTION92

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