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- PDB-6ecq: The human methylenetetrahydrofolate dehydrogenase/cyclohydrolase ... -

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Basic information

Entry
Database: PDB / ID: 6ecq
TitleThe human methylenetetrahydrofolate dehydrogenase/cyclohydrolase (FolD) complexed with NADP and inhibitor LY345899
ComponentsMETHYLENETETRAHYDROFOLATE DEHYDROGENASE CYCLOHYDROLASE
KeywordsOXIDOREDUCTASE / dehydrogenase / cyclohydrolase / bifunctional protein
Function / homology
Function and homology information


methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity / serine family amino acid biosynthetic process / 10-formyltetrahydrofolate biosynthetic process / purine ribonucleotide biosynthetic process / serine family amino acid metabolic process / methylenetetrahydrofolate dehydrogenase (NAD+) activity / formate-tetrahydrofolate ligase / formate-tetrahydrofolate ligase activity / methylenetetrahydrofolate dehydrogenase (NADP+) / embryonic neurocranium morphogenesis ...methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity / serine family amino acid biosynthetic process / 10-formyltetrahydrofolate biosynthetic process / purine ribonucleotide biosynthetic process / serine family amino acid metabolic process / methylenetetrahydrofolate dehydrogenase (NAD+) activity / formate-tetrahydrofolate ligase / formate-tetrahydrofolate ligase activity / methylenetetrahydrofolate dehydrogenase (NADP+) / embryonic neurocranium morphogenesis / methenyltetrahydrofolate cyclohydrolase / methenyltetrahydrofolate cyclohydrolase activity / embryonic viscerocranium morphogenesis / methylenetetrahydrofolate dehydrogenase (NADP+) activity / methionine metabolic process / somite development / methionine biosynthetic process / Metabolism of folate and pterines / transsulfuration / neutrophil homeostasis / purine nucleotide biosynthetic process / tetrahydrofolate interconversion / neural tube closure / one-carbon metabolic process / 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
Chem-LUD / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / C-1-tetrahydrofolate synthase, cytoplasmic
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.7 Å
AuthorsBueno, R.V. / Dawson, A. / Hunter, W.N.
Funding support Brazil, 1items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP)2016/16038-5 Brazil
CitationJournal: Biochemistry / Year: 2000
Title: Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
Authors: Schmidt, A. / Wu, H. / MacKenzie, R.E. / Chen, V.J. / Bewly, J.R. / Ray, J.E. / Toth, J.E. / Cygler, M.
History
DepositionAug 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Remark 0THIS ENTRY 6ECQ REFLECTS AN ALTERNATIVE MODELING OF THE ORIGINAL DATA IN 1DIB, DETERMINED BY A. ...THIS ENTRY 6ECQ REFLECTS AN ALTERNATIVE MODELING OF THE ORIGINAL DATA IN 1DIB, DETERMINED BY A.Schmidt,H.Wu,R.E.MacKenzie,V.J.Chen,J.R.Bewly,J.E.Ray,J.E.Toth,M.Cygler

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: METHYLENETETRAHYDROFOLATE DEHYDROGENASE CYCLOHYDROLASE
B: METHYLENETETRAHYDROFOLATE DEHYDROGENASE CYCLOHYDROLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,1405
Polymers64,1822
Non-polymers1,9583
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4930 Å2
ΔGint-14 kcal/mol
Surface area24240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.490, 136.370, 61.380
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: 0 / Auth seq-ID: 2 - 296 / Label seq-ID: 2 - 296

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein METHYLENETETRAHYDROFOLATE DEHYDROGENASE CYCLOHYDROLASE / C1-THF synthase


Mass: 32090.848 Da / Num. of mol.: 2
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, methylenetetrahydrofolate dehydrogenase (NADP+), methenyltetrahydrofolate cyclohydrolase, formate-tetrahydrofolate ligase
#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-LUD / N-{4-[(6aR)-3-amino-1,9-dioxo-1,2,5,6,6a,7-hexahydroimidazo[1,5-f]pteridin-8(9H)-yl]benzene-1-carbonyl}-L-glutamic acid


Mass: 471.423 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N7O7
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / Source method: isolated from a natural source / Formula: H2O

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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: 2.2 Å3/Da / Density % sol: 44.1 % / Description: AUTHOR USED THE SF DATA FROM ENTRY 1DIA
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: PEG 3350, GLYCEROL, SODIUM CITRATE, AMMONIUM ACETATE, pH 5.2, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 20K.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.7→20 Å / Num. all: 15688 / Num. obs: 15688 / % possible obs: 97.1 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 5 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 3
Reflection shellResolution: 2.7→2.74 Å / Redundancy: 5 % / Rmerge(I) obs: 0.332 / % possible all: 95.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
DENZOdata reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1DIB

1dib


Resolution: 2.7→19.6 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.871 / SU B: 13.439 / SU ML: 0.271 / Cross valid method: THROUGHOUT / ESU R Free: 0.41 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24725 1548 10.1 %RANDOM
Rwork0.17905 ---
obs0.18592 13706 94.37 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.615 Å2
Baniso -1Baniso -2Baniso -3
1--0.22 Å20 Å20 Å2
2--0.55 Å2-0 Å2
3----0.33 Å2
Refinement stepCycle: 1 / Resolution: 2.7→19.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4412 0 130 100 4642
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194621
X-RAY DIFFRACTIONr_bond_other_d0.0010.024386
X-RAY DIFFRACTIONr_angle_refined_deg1.551.9736293
X-RAY DIFFRACTIONr_angle_other_deg0.963310218
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9755579
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.22425.506178
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.58715800
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9271523
X-RAY DIFFRACTIONr_chiral_restr0.0820.2747
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215290
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02793
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2922.3692326
X-RAY DIFFRACTIONr_mcbond_other1.292.3672325
X-RAY DIFFRACTIONr_mcangle_it2.183.5422901
X-RAY DIFFRACTIONr_mcangle_other2.1813.5432902
X-RAY DIFFRACTIONr_scbond_it1.5312.6982295
X-RAY DIFFRACTIONr_scbond_other1.5322.72293
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.6143.9693393
X-RAY DIFFRACTIONr_long_range_B_refined4.39329.0054879
X-RAY DIFFRACTIONr_long_range_B_other4.37729.0194870
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 17084 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.7→2.769 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 91 -
Rwork0.25 884 -
obs--86.05 %

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