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- PDB-9isl: Human MTHFD1 in complex with compound 16e -

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Basic information

Entry
Database: PDB / ID: 9isl
TitleHuman MTHFD1 in complex with compound 16e
ComponentsC-1-tetrahydrofolate synthase, cytoplasmic
KeywordsOXIDOREDUCTASE / MTHFD1 / methylenetetrahydrofolate dehydrogenase/cyclohydrolase
Function / homology
Function and homology information


: / purine ribonucleotide biosynthetic process / formate-tetrahydrofolate ligase / formate-tetrahydrofolate ligase activity / methylenetetrahydrofolate dehydrogenase (NAD+) activity / methylenetetrahydrofolate dehydrogenase (NADP+) / embryonic neurocranium morphogenesis / embryonic viscerocranium morphogenesis / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity ...: / purine ribonucleotide biosynthetic process / formate-tetrahydrofolate ligase / formate-tetrahydrofolate ligase activity / methylenetetrahydrofolate dehydrogenase (NAD+) activity / methylenetetrahydrofolate dehydrogenase (NADP+) / embryonic neurocranium morphogenesis / embryonic viscerocranium morphogenesis / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity / methionine metabolic process / methylenetetrahydrofolate dehydrogenase (NADP+) activity / somite development / 10-formyltetrahydrofolate biosynthetic process / transsulfuration / Metabolism of folate and pterines / neutrophil homeostasis / methionine biosynthetic process / purine nucleotide biosynthetic process / tetrahydrofolate interconversion / folic acid metabolic process / neural tube closure / heart development / mitochondrion / extracellular exosome / ATP binding / membrane / cytosol
Similarity search - Function
Formate-tetrahydrofolate ligase, FTHFS / Formate-tetrahydrofolate ligase, FTHFS, conserved site / Formate--tetrahydrofolate ligase / Formate--tetrahydrofolate ligase signature 1. / Formate--tetrahydrofolate ligase signature 2. / Tetrahydrofolate dehydrogenase/cyclohydrolase signature 1. / Tetrahydrofolate dehydrogenase/cyclohydrolase signature 2. / Tetrahydrofolate dehydrogenase/cyclohydrolase, conserved site / Tetrahydrofolate dehydrogenase/cyclohydrolase / Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain ...Formate-tetrahydrofolate ligase, FTHFS / Formate-tetrahydrofolate ligase, FTHFS, conserved site / Formate--tetrahydrofolate ligase / Formate--tetrahydrofolate ligase signature 1. / Formate--tetrahydrofolate ligase signature 2. / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / C-1-tetrahydrofolate synthase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 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 18, 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: C-1-tetrahydrofolate synthase, cytoplasmic
B: C-1-tetrahydrofolate synthase, cytoplasmic
C: C-1-tetrahydrofolate synthase, cytoplasmic
D: C-1-tetrahydrofolate synthase, cytoplasmic
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,73212
Polymers134,8874
Non-polymers4,8458
Water6,305350
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4920 Å2
ΔGint-15 kcal/mol
Surface area22600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.020, 200.679, 240.140
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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Components

#1: Protein
C-1-tetrahydrofolate synthase, cytoplasmic / C1-THF synthase / Epididymis secretory sperm binding protein


Mass: 33721.688 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTHFD1, MTHFC, MTHFD / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P11586
#2: Chemical
ChemComp-A1L23 / (2~{S})-2-[[4-[[2,4-bis(azanyl)-6-oxidanylidene-1~{H}-pyrimidin-5-yl]carbamoylamino]-3-chloranyl-phenyl]carbonylamino]pentanedioic acid


Mass: 467.821 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H18ClN7O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 2.92 Å3/Da / Density % sol: 57.81 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: 0.09 M NPS, Morpheus Buffer System 2 pH 7.5, 42% Morpheus Precipitant Mix 4

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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: May 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.06→30 Å / Num. obs: 96188 / % possible obs: 98.9 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.057 / Net I/σ(I): 13.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.06-2.133.40.62595930.6160.8730.3950.7411.008100
2.13-2.223.40.43896400.7730.9340.2760.521.049100
2.22-2.323.40.31196390.8690.9640.1970.3691.05499.9
2.32-2.443.40.23695360.9250.980.1490.2791.01799.3
2.44-2.63.40.17496480.9570.9890.110.2061.07299.4
2.6-2.83.40.1296290.9770.9940.0760.1431.01499.8
2.8-3.083.40.07996650.9910.9980.050.0931.00699.5
3.08-3.523.30.05495890.9950.9990.0350.0651.04898.4
3.52-4.433.30.03396170.9970.9990.0220.041.01497.9
4.43-303.30.02296320.99910.0140.0261.05895.1

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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: 2.06→29.69 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 25.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2502 4928 5.13 %
Rwork0.2064 --
obs0.2086 96156 98.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.06→29.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8588 0 320 350 9258
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008
X-RAY DIFFRACTIONf_angle_d1.01
X-RAY DIFFRACTIONf_dihedral_angle_d19.0323517
X-RAY DIFFRACTIONf_chiral_restr0.0611470
X-RAY DIFFRACTIONf_plane_restr0.0081571
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.06-2.080.32081720.29922854X-RAY DIFFRACTION95
2.08-2.110.34442050.28733039X-RAY DIFFRACTION100
2.11-2.130.3371450.29043025X-RAY DIFFRACTION100
2.13-2.160.3351710.27983073X-RAY DIFFRACTION100
2.16-2.190.36381680.26623029X-RAY DIFFRACTION100
2.19-2.220.2761470.26013053X-RAY DIFFRACTION100
2.22-2.250.31551420.24983069X-RAY DIFFRACTION100
2.25-2.280.31081560.24753064X-RAY DIFFRACTION100
2.28-2.320.30341510.24953055X-RAY DIFFRACTION100
2.32-2.360.31721600.24893017X-RAY DIFFRACTION99
2.36-2.40.3181810.24123059X-RAY DIFFRACTION99
2.4-2.440.28671550.24843004X-RAY DIFFRACTION99
2.44-2.490.271640.23923044X-RAY DIFFRACTION99
2.49-2.540.27851740.23533028X-RAY DIFFRACTION99
2.54-2.590.28871550.22993073X-RAY DIFFRACTION100
2.59-2.660.2831650.23213036X-RAY DIFFRACTION100
2.66-2.720.27381780.23033067X-RAY DIFFRACTION100
2.72-2.80.26121670.22033061X-RAY DIFFRACTION100
2.8-2.880.2881750.23363034X-RAY DIFFRACTION100
2.88-2.970.3111670.23463073X-RAY DIFFRACTION99
2.97-3.080.25421510.22153057X-RAY DIFFRACTION99
3.08-3.20.24631460.2183096X-RAY DIFFRACTION99
3.2-3.340.26381700.21133008X-RAY DIFFRACTION98
3.34-3.520.24581700.20253024X-RAY DIFFRACTION98
3.52-3.740.2291700.19043005X-RAY DIFFRACTION98
3.74-4.030.22161700.18163073X-RAY DIFFRACTION98
4.03-4.430.20171840.16143036X-RAY DIFFRACTION98
4.43-5.070.20561440.16173079X-RAY DIFFRACTION97
5.07-6.380.2131540.18993101X-RAY DIFFRACTION97
6.38-29.690.1931710.16442992X-RAY DIFFRACTION91

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