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- PDB-9itd: Human MTHFD1 in complex with compound 16a -

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Basic information

Entry
Database: PDB / ID: 9itd
TitleHuman MTHFD1 in complex with compound 16a
ComponentsC-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
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: 2.28 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

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Assembly

Deposited unit
A: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
B: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
C: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
D: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,16512
Polymers134,3624
Non-polymers4,8038
Water3,243180
1
A: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
B: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,5836
Polymers67,1812
Non-polymers2,4024
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4900 Å2
ΔGint-15 kcal/mol
Surface area22530 Å2
MethodPISA
2
C: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
D: C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,5836
Polymers67,1812
Non-polymers2,4024
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4940 Å2
ΔGint-16 kcal/mol
Surface area23230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.296, 200.343, 239.744
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, N-terminally processed


Mass: 33590.488 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-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#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.: 4 / Source method: obtained synthetically / Formula: C17H19N11O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / 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: 57.84 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, hanging drop
Details: NPS, Morpheus Buffer System 2, Morpheus Precipitant Mix 4

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: TPS 05A / Wavelength: 0.99984 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Dec 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99984 Å / Relative weight: 1
ReflectionResolution: 2.28→30 Å / Num. obs: 72243 / % possible obs: 99.4 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.28-2.363.10.58471530.5770.8550.3850.7031.01999.6
2.36-2.463.60.54271710.690.9040.3190.6311.022100
2.46-2.573.80.42671960.7990.9420.2430.4921.048100
2.57-2.73.80.30172210.8880.970.1720.3481.099100
2.7-2.873.80.21771920.9370.9840.1250.2511.072100
2.87-3.093.80.14372350.9720.9930.0820.1651.097100
3.09-3.43.80.09172380.9890.9970.0530.1051.061100
3.4-3.93.70.06772710.9920.9980.040.0781.07599.8
3.9-4.913.70.04473170.9960.9990.0260.0521.01999.8
4.91-303.70.0372490.99910.0180.0351.0495.4

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286_000refinement
SCALEPACKdata scaling
HKL-2000data reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.28→26.21 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 32.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2993 3604 5 %
Rwork0.2368 --
obs0.2399 72100 98.78 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.28→26.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8676 0 324 180 9180
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01
X-RAY DIFFRACTIONf_angle_d1.048
X-RAY DIFFRACTIONf_dihedral_angle_d17.9483578
X-RAY DIFFRACTIONf_chiral_restr0.061479
X-RAY DIFFRACTIONf_plane_restr0.0081587
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.28-2.30.41391310.342226X-RAY DIFFRACTION85
2.3-2.330.36611230.33692680X-RAY DIFFRACTION99
2.33-2.370.38011340.31892565X-RAY DIFFRACTION100
2.37-2.40.40191480.32192643X-RAY DIFFRACTION100
2.4-2.440.38721340.33232621X-RAY DIFFRACTION100
2.44-2.480.37631370.31322603X-RAY DIFFRACTION100
2.48-2.520.37631370.30912683X-RAY DIFFRACTION100
2.52-2.570.37031280.30542627X-RAY DIFFRACTION100
2.57-2.620.35531480.29982628X-RAY DIFFRACTION100
2.62-2.670.33821430.29282617X-RAY DIFFRACTION100
2.67-2.730.32651380.29282680X-RAY DIFFRACTION100
2.73-2.790.35791490.29182621X-RAY DIFFRACTION100
2.79-2.860.36191450.29912656X-RAY DIFFRACTION100
2.86-2.940.40611510.28342618X-RAY DIFFRACTION100
2.94-3.020.32561300.27852657X-RAY DIFFRACTION100
3.02-3.120.34421510.26772652X-RAY DIFFRACTION100
3.12-3.230.33381410.26722659X-RAY DIFFRACTION100
3.23-3.360.3181320.25312664X-RAY DIFFRACTION100
3.36-3.510.29271310.23842679X-RAY DIFFRACTION100
3.51-3.70.26741490.22312650X-RAY DIFFRACTION100
3.7-3.930.31111590.21952658X-RAY DIFFRACTION100
3.93-4.230.27431260.20322701X-RAY DIFFRACTION100
4.23-4.660.26921190.18242729X-RAY DIFFRACTION100
4.66-5.330.23431470.18262702X-RAY DIFFRACTION100
5.33-6.690.22151480.1892673X-RAY DIFFRACTION98
6.69-26.210.17921250.14582604X-RAY DIFFRACTION91

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