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- PDB-9isr: Human MTHFD1 in complex with compound 16g -

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Basic information

Entry
Database: PDB / ID: 9isr
TitleHuman MTHFD1 in complex with compound 16g
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: 2.5 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

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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)139,30312
Polymers134,3624
Non-polymers4,9418
Water2,630146
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)69,6516
Polymers67,1812
Non-polymers2,4714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4970 Å2
ΔGint-15 kcal/mol
Surface area22600 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)69,6516
Polymers67,1812
Non-polymers2,4714
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-14 kcal/mol
Surface area22990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.075, 201.469, 240.021
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-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.: 4 / Source method: obtained synthetically / Formula: C17H18ClN11O5
#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.: 146 / 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: 2.93 Å3/Da / Density % sol: 57.99 %
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: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: May 26, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.5→30 Å / Num. obs: 52966 / % possible obs: 96.3 % / Redundancy: 5.4 % / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.046 / Rrim(I) all: 0.112 / Χ2: 1.046 / Net I/σ(I): 10.2 / Num. measured all: 283980
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
2.5-2.595.30.92650020.5460.840.4181.021.00992.5
2.59-2.695.10.66250200.6970.9060.3090.7331.02592.6
2.69-2.8250.48650780.8030.9440.2280.5391.01293.3
2.82-2.965.40.34551660.9120.9770.1550.3791.03294.8
2.96-3.155.10.21953150.9540.9880.1030.2431.03797.7
3.15-3.395.60.14454210.9840.9960.0630.1581.05198.8
3.39-3.735.70.09654410.9910.9980.0430.1051.07199.3
3.73-4.275.60.06754910.9950.9990.030.0741.08999.3
4.27-5.385.20.04954920.9960.9990.0230.0551.04898.5
5.38-305.50.03755400.99910.0170.0411.06695.9

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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: 2.5→30 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.9 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2637 2693 5.09 %
Rwork0.2128 --
obs0.2154 52903 95.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8576 0 328 146 9050
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009
X-RAY DIFFRACTIONf_angle_d1.137
X-RAY DIFFRACTIONf_dihedral_angle_d20.1983508
X-RAY DIFFRACTIONf_chiral_restr0.0621475
X-RAY DIFFRACTIONf_plane_restr0.0131562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.5-2.540.41011230.31172287X-RAY DIFFRACTION85
2.54-2.590.34061430.30252510X-RAY DIFFRACTION92
2.59-2.650.36141110.29842577X-RAY DIFFRACTION93
2.65-2.70.39541340.29832504X-RAY DIFFRACTION92
2.7-2.770.35631410.29352532X-RAY DIFFRACTION94
2.77-2.830.3351220.28792560X-RAY DIFFRACTION94
2.83-2.910.3431390.27062587X-RAY DIFFRACTION95
2.91-30.31111480.2582616X-RAY DIFFRACTION96
3-3.090.31331320.2562675X-RAY DIFFRACTION97
3.09-3.20.31551480.26362703X-RAY DIFFRACTION99
3.2-3.330.31471360.24652709X-RAY DIFFRACTION99
3.33-3.480.25791550.22042713X-RAY DIFFRACTION99
3.48-3.670.27581470.21512740X-RAY DIFFRACTION99
3.67-3.90.24921600.20082729X-RAY DIFFRACTION99
3.9-4.20.24181440.18422737X-RAY DIFFRACTION99
4.2-4.620.21031610.16582774X-RAY DIFFRACTION99
4.62-5.280.21871570.16632709X-RAY DIFFRACTION98
5.28-6.640.23111440.18922769X-RAY DIFFRACTION97
6.65-300.18891480.15332779X-RAY DIFFRACTION95

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