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- PDB-4m6l: Crystal structure of human dihydrofolate reductase (DHFR) bound t... -

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Basic information

Entry
Database: PDB / ID: 4m6l
TitleCrystal structure of human dihydrofolate reductase (DHFR) bound to NADP+ and 5,10-dideazatetrahydrofolic acid
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE / Rossmann Fold / NADPH binding / folate binding
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / dihydrofolate metabolic process / axon regeneration / folic acid binding / G1/S-Specific Transcription ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / dihydrofolate metabolic process / axon regeneration / folic acid binding / G1/S-Specific Transcription / folic acid metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / NADPH binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / tetrahydrofolate biosynthetic process / mRNA regulatory element binding translation repressor activity / positive regulation of nitric-oxide synthase activity / one-carbon metabolic process / NADP binding / negative regulation of translation / mRNA binding / mitochondrion / cytosol
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-21V / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsBhabha, G. / Ekiert, D.C. / Wright, P.E. / Wilson, I.A.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2013
Title: Divergent evolution of protein conformational dynamics in dihydrofolate reductase.
Authors: Bhabha, G. / Ekiert, D.C. / Jennewein, M. / Zmasek, C.M. / Tuttle, L.M. / Kroon, G. / Dyson, H.J. / Godzik, A. / Wilson, I.A. / Wright, P.E.
History
DepositionAug 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2013Group: Database references
Revision 1.2Nov 20, 2013Group: Database references
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,9185
Polymers21,4811
Non-polymers1,4374
Water2,576143
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.781, 67.781, 160.408
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number182
Space group name H-MP6322
Components on special symmetry positions
IDModelComponents
11A-341-

HOH

21A-343-

HOH

31A-360-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dihydrofolate reductase /


Mass: 21480.723 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR / Plasmid: pET21A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)/PDNAY / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 5 types, 147 molecules

#2: Chemical ChemComp-21V / N-(4-{2-[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl}benzoyl)-L-glutamic acid / 5,10-dideazatetrahydrofolic acid


Mass: 443.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H25N5O6
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE / Nicotinamide adenine dinucleotide phosphate


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#4: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#5: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 2.48 Å3/Da / Density % sol: 50.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4
Details: 2.2 M ammonium sulfate, 100 mM sodium citrate, pH 4.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 29, 2010
RadiationMonochromator: Double crystal cryo-cooled Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 24905 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 18.3 % / Rsym value: 0.13 / Net I/σ(I): 25.4
Reflection shellResolution: 1.7→1.73 Å / Redundancy: 18.3 % / Mean I/σ(I) obs: 2.2 / Rsym value: 0.85 / % possible all: 99.3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.8.2_1309)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4M6J

4m6j


Resolution: 1.7→47.369 Å / SU ML: 0.21 / σ(F): 1.33 / Phase error: 25.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2398 1256 5.1 %RANDOM
Rwork0.1921 ---
obs0.1944 24628 99.01 %-
Solvent computationShrinkage radii: 0.6 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 34.7 Å2
Refinement stepCycle: LAST / Resolution: 1.7→47.369 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1502 0 93 143 1738
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071680
X-RAY DIFFRACTIONf_angle_d1.2482286
X-RAY DIFFRACTIONf_dihedral_angle_d15.309659
X-RAY DIFFRACTIONf_chiral_restr0.075242
X-RAY DIFFRACTIONf_plane_restr0.005288
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.76810.36931240.35462472X-RAY DIFFRACTION97
1.7681-1.84860.31031430.31242492X-RAY DIFFRACTION98
1.8486-1.9460.30271500.25182501X-RAY DIFFRACTION98
1.946-2.06790.25851190.19982581X-RAY DIFFRACTION99
2.0679-2.22760.21111490.19182557X-RAY DIFFRACTION100
2.2276-2.45180.24341490.18782587X-RAY DIFFRACTION100
2.4518-2.80650.24131500.18622621X-RAY DIFFRACTION100
2.8065-3.53570.22791370.17012674X-RAY DIFFRACTION100
3.5357-47.38710.21671350.17182887X-RAY DIFFRACTION100
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)
10.6482-0.2537-0.12780.31330.6070.67480.0865-0.09630.0939-0.0586-0.0107-0.1027-0.2291-0.04160.0370.30030.04530.02240.12-0.00550.177526.87455.1534-29.0339
21.21130.23680.31770.2740.04471.92620.0952-0.16690.04210.1345-0.05740.1635-0.3093-0.15230.03410.29020.05110.03720.1617-0.01290.183123.72032.612-14.7877
30.0412-0.0370.05660.0123-0.04460.05170.2062-0.4178-0.31270.31790.2784-0.17120.0728-0.3664-0.00040.4234-0.0186-0.02760.3672-0.01010.243126.4376-7.7054-5.8318
40.7131-0.1612-0.67980.92690.16370.88550.1135-0.14950.058-0.0714-0.0428-0.0585-0.23720.24480.02570.2366-0.00780.0190.1401-0.00130.176534.16250.4776-27.8213
50.55050.0294-0.7329-0.06380.27440.93490.0544-0.0011-0.182-0.07740.03740.08120.0313-0.0130.05060.17840.0507-0.00730.10920.01260.217426.0632-6.7001-34.141
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1 through 27 )
2X-RAY DIFFRACTION2chain 'A' and (resid 28 through 101 )
3X-RAY DIFFRACTION3chain 'A' and (resid 102 through 111 )
4X-RAY DIFFRACTION4chain 'A' and (resid 112 through 158 )
5X-RAY DIFFRACTION5chain 'A' and (resid 159 through 186 )

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