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- PDB-5tc4: Crystal structure of human mitochondrial methylenetetrahydrofolat... -

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Basic information

Entry
Database: PDB / ID: 5tc4
TitleCrystal structure of human mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (MTHFD2) in complex with LY345899 and cofactors
ComponentsBifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
KeywordsOXIDOREDUCTASE / Inhibitor / Folate / Cofactor / Dehydrogenase
Function / homology
Function and homology information


methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / 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 ...methylenetetrahydrofolate dehydrogenase (NAD+) / methylenetetrahydrofolate dehydrogenase (NAD+) activity / 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 / Leucine Dehydrogenase, chain A, domain 1 / Aminoacid dehydrogenase-like, N-terminal domain superfamily ...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 / Leucine Dehydrogenase, chain A, domain 1 / Aminoacid dehydrogenase-like, N-terminal domain superfamily / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-L34 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / PHOSPHATE ION / Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsGustafsson, R. / Jemth, A.-S. / Gustafsson Sheppard, N. / Farnegardh, K. / Loseva, O. / Wiita, E. / Bonagas, N. / Dahllund, L. / Llona-Minguez, S. / Haggblad, M. ...Gustafsson, R. / Jemth, A.-S. / Gustafsson Sheppard, N. / Farnegardh, K. / Loseva, O. / Wiita, E. / Bonagas, N. / Dahllund, L. / Llona-Minguez, S. / Haggblad, M. / Henriksson, M. / Andersson, Y. / Homan, E. / Helleday, T. / Stenmark, P.
Funding support Sweden, 13items
OrganizationGrant numberCountry
Swedish Research Council Sweden
Knut and Alice Wallenberg Foundation Sweden
Wenner-Gren Foundation Sweden
Goran Gustafsson's Foundation for Science and Medical Research Sweden
Svenska Smartafonden Sweden
Ragnar Soderberg Foundation Sweden
Swedish Childhood Cancer Foundation Sweden
Svenska Sallskapet for Medicinsk Forskning (SSMF) Sweden
Karolinska Institutet (KI) Sweden
Helleday Foundation Sweden
Swedish Cancer Society Sweden
Torsten Soderberg Foundation Sweden
Ake Wiberg Foundation Sweden
CitationJournal: Cancer Res. / Year: 2017
Title: Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor.
Authors: Gustafsson, R. / Jemth, A.S. / Gustafsson, N.M. / Farnegardh, K. / Loseva, O. / Wiita, E. / Bonagas, N. / Dahllund, L. / Llona-Minguez, S. / Haggblad, M. / Henriksson, M. / Andersson, Y. / ...Authors: Gustafsson, R. / Jemth, A.S. / Gustafsson, N.M. / Farnegardh, K. / Loseva, O. / Wiita, E. / Bonagas, N. / Dahllund, L. / Llona-Minguez, S. / Haggblad, M. / Henriksson, M. / Andersson, Y. / Homan, E. / Helleday, T. / Stenmark, P.
History
DepositionSep 14, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 14, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2017Group: Database references
Revision 1.2Aug 16, 2017Group: Data collection / Category: diffrn_source
Item: _diffrn_source.pdbx_synchrotron_beamline / _diffrn_source.type
Revision 1.3Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 17, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5454
Polymers34,3151
Non-polymers1,2303
Water3,855214
1
A: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
hetero molecules

A: Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,0898
Polymers68,6292
Non-polymers2,4606
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_855-x+3,-y,z1
Buried area6150 Å2
ΔGint-49 kcal/mol
Surface area23020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.323, 74.323, 98.620
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number79
Space group name H-MI4
Components on special symmetry positions
IDModelComponents
11A-599-

HOH

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Components

#1: Protein Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial


Mass: 34314.746 Da / Num. of mol.: 1 / Fragment: UNP Residues 36-350
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-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical ChemComp-L34 / 4-(7-AMINO-9-HYDROXY-1-OXO-3,3A,4,5-TETRAHYDRO-2,5,6,8,9B-PENTAAZA-CYCLOPENTA[A]NAPHTHALEN-2-YL)-PHENYLCARBONYL-GLUTAMI C ACID / LY345899


Mass: 471.423 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N7O7
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 214 / 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: 1.98 Å3/Da / Density % sol: 38.02 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Phosphate/Citrate pH 4.1, 38 % v/v PEG300, in presence of 1:50 ratio each of trypsin, alpha-chymotrypsin, pepsin, papain, proteinase K and subtilisin to MTHFD2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-3 / Wavelength: 0.9677 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 3, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9677 Å / Relative weight: 1
ReflectionResolution: 1.89→37.16 Å / Num. obs: 21322 / % possible obs: 99.8 % / Redundancy: 6.9 % / CC1/2: 0.98 / Rmerge(I) obs: 0.316 / Net I/σ(I): 6.8
Reflection shellResolution: 1.89→1.93 Å / Redundancy: 6.7 % / Rmerge(I) obs: 4.348 / Mean I/σ(I) obs: 0.9 / CC1/2: 0.297 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1B0A

1b0a


Resolution: 1.89→37.16 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.946 / SU B: 9.818 / SU ML: 0.139 / Cross valid method: THROUGHOUT / ESU R: 0.158 / ESU R Free: 0.145 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21222 1073 5 %RANDOM
Rwork0.1626 ---
obs0.16509 20245 99.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.27 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å20 Å20 Å2
2--0.04 Å20 Å2
3----0.08 Å2
Refinement stepCycle: 1 / Resolution: 1.89→37.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2216 0 83 214 2513
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0192379
X-RAY DIFFRACTIONr_bond_other_d0.0020.022346
X-RAY DIFFRACTIONr_angle_refined_deg2.2762.0063244
X-RAY DIFFRACTIONr_angle_other_deg1.1735401
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0425296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.82724.77890
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.23615410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2671514
X-RAY DIFFRACTIONr_chiral_restr0.1370.2377
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212646
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02497
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_it0.9011.2951184
X-RAY DIFFRACTIONr_mcbond_other0.8971.2951184
X-RAY DIFFRACTIONr_mcangle_it1.431.9271480
X-RAY DIFFRACTIONr_mcangle_other1.4311.931481
X-RAY DIFFRACTIONr_scbond_it1.6421.6631195
X-RAY DIFFRACTIONr_scbond_other1.641.6631192
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.6022.4121759
X-RAY DIFFRACTIONr_long_range_B_refined6.25312.4522789
X-RAY DIFFRACTIONr_long_range_B_other6.06611.8352715
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.893→1.942 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 71 -
Rwork0.348 1463 -
obs--97.4 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.93961.0531-5.99991.2393-3.55920.9785-0.09550.30220.0086-0.0205-0.11280.2910.1668-0.88430.20830.0726-0.023-0.01140.2043-0.08140.23784.40539.5968-2.9965
20.50460.46440.23871.12660.25560.2349-0.0815-0.03630.10790.17640.00590.1258-0.03670.00320.07570.19520.03620.02650.1584-0.0020.043699.169617.970814.3693
30.03050.07360.00370.35820.43511.2147-0.0027-0.00940.03110.0935-0.04490.09770.0599-0.00370.04760.1881-0.00190.02080.1583-0.00040.0419102.31124.13135.7143
40.65480.0098-0.11590.6972-0.10430.48340.01840.07960.00560.0062-0.00290.0631-0.0014-0.0026-0.01540.17030.0047-0.01110.1630.0080.0204105.08764.8474-12.7991
53.6544-9.24382.631433.9544-1.17984.7511-0.6429-0.4810.42080.6170.3327-1.1395-0.9317-0.80340.31030.38380.16890.16620.1374-0.05480.544101.37528.4525-10.3762
61.1838-0.28-1.00080.42560.22053.87270.07740.09290.2825-0.1298-0.07510.20080.0423-0.0237-0.00230.11980.0415-0.06170.10320.00160.290695.085214.6726-13.7554
71.29741.3564-1.70215.2598-2.02329.452-0.0191-0.1073-0.2726-0.0232-0.00220.12250.69350.1980.02130.1655-0.00850.03960.1476-0.01720.165492.31623.778512.0475
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A36 - 59
2X-RAY DIFFRACTION2A60 - 142
3X-RAY DIFFRACTION3A143 - 185
4X-RAY DIFFRACTION4A186 - 275
5X-RAY DIFFRACTION5A276 - 289
6X-RAY DIFFRACTION6A290 - 320
7X-RAY DIFFRACTION7A321 - 332

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