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- PDB-5sda: Crystal Structure of Dihydrofolate Reductase from Homo sapiens bo... -

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Basic information

Entry
Database: PDB / ID: 5sda
TitleCrystal Structure of Dihydrofolate Reductase from Homo sapiens bound to NADP and SDDC Inhibitor SDDC-774
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Homo sapiens / DHFR / NADP / Folate / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to methotrexate / sequence-specific mRNA binding / axon regeneration / folic acid binding / dihydrofolate metabolic process / G1/S-Specific Transcription ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / response to methotrexate / sequence-specific mRNA binding / axon regeneration / folic acid binding / dihydrofolate metabolic process / G1/S-Specific Transcription / folic acid metabolic 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 / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily
Similarity search - Domain/homology
Chem-GI6 / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsSeattle Structural Genomics Center for Infectious Disease (SSGCID)
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201700059C United States
CitationJournal: to be published
Title: Crystal Structure of Dihydrofolate Reductase from Homo sapiens bound to NADP and SDDC Inhibitor SDDC-774
Authors: Mayclin, S.J. / Fairman, J.W. / Dranow, D.M. / Conrady, D.G. / Fox III, D. / Lukacs, C.M. / Lorimer, D.D. / Horanyi, P.S. / Edwards, T.E. / Abendroth, J.
History
DepositionDec 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 2, 2022Group: Other / Structure summary
Category: pdbx_SG_project / pdbx_database_status / struct_keywords
Item: _pdbx_database_status.SG_entry / _struct_keywords.text
Revision 1.2May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,0459
Polymers21,4811
Non-polymers1,5658
Water1,910106
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.300, 74.300, 143.630
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-329-

HOH

21A-349-

HOH

Detailsbiological unit is a monomer, the same as asu

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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 / Fragment: Human DHFR
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DHFR / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 6 types, 114 molecules

#2: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#3: Chemical ChemComp-GI6 / (2R)-3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)-2-methylpropanamide


Mass: 373.449 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 4.61 Å3/Da / Density % sol: 73.34 % / Mosaicity: 0.17 °
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: MCSG2 E5 (273949e5): 200mM Lithium sulfate, 100mM Sodium acetate:acetic acid pH4.5, 30% (w/v) PEG8000; prot conc 26mg/mL, cryo 20% EG, puck ogi6-2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jul 15, 2016
RadiationMonochromator: C111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.45→50 Å / Num. obs: 15383 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 36.831 Å2 / Rmerge F obs: 0.998 / Rmerge(I) obs: 0.088 / Rrim(I) all: 0.094 / Net I/σ(I): 19.59 / Num. measured all: 121264
Reflection shell
Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.45-2.510.9030.4724.359105111911190.503100
2.51-2.580.9110.434.928816108910890.459100
2.58-2.660.950.3396.188653106810670.36199.9
2.66-2.740.9570.3036.98344102410240.323100
2.74-2.830.9730.2358.6580059949920.25199.8
2.83-2.930.9790.20210.1377459709670.21699.7
2.93-3.040.9890.16612.3275209329280.17799.6
3.04-3.160.9910.1414.7272039049010.14999.7
3.16-3.30.9940.1117.6369358848810.11899.7
3.3-3.460.9960.08522.4763568198160.09199.6
3.46-3.650.9980.06427.7661418037990.06999.5
3.65-3.870.9980.0629.557947597560.06499.6
3.87-4.140.9980.04934.3255897287230.05399.3
4.14-4.470.9990.04537.6650906636570.04899.1
4.47-4.90.9990.03940.548086246180.04299
4.9-5.480.9990.0438.8943025615550.04298.9
5.48-6.330.9990.04236.3338885145060.04598.4
6.33-7.750.9990.04336.6432334374290.04798.2
7.75-10.960.9990.03147.6125073613510.03497.2
10.960.9980.03244.5512302182050.03594

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIXdev_2481refinement
PDB_EXTRACT3.11data extraction
PHENIXmodel building
Cootmodel building
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→49.341 Å / Occupancy max: 1 / Occupancy min: 0 / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 18.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2054 1468 9.55 %
Rwork0.161 13911 -
obs0.1652 15379 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 92.99 Å2 / Biso mean: 34.7762 Å2 / Biso min: 10.85 Å2
Refinement stepCycle: LAST / Resolution: 2.45→49.341 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1486 0 99 106 1691
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081693
X-RAY DIFFRACTIONf_angle_d1.0112311
X-RAY DIFFRACTIONf_chiral_restr0.058243
X-RAY DIFFRACTIONf_plane_restr0.005291
X-RAY DIFFRACTIONf_dihedral_angle_d10.1291714
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.45-2.53760.26581480.196313551503100
2.5376-2.63920.23881310.193813841515100
2.6392-2.75930.24781210.183413981519100
2.7593-2.90480.25521470.184213541501100
2.9048-3.08670.24371570.185113731530100
3.0867-3.3250.25521530.175613621515100
3.325-3.65950.17781590.15113651524100
3.6595-4.18880.16841320.141114201552100
4.1888-5.27650.1771390.1261429156899
5.2765-49.35070.18591810.16891471165298
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)
12.69390.1466-0.41915.1802-0.33194.7842-0.0757-0.03450.0854-0.02750.0845-0.00350.0577-0.0877-0.00130.1414-0.0234-0.00430.1740.01060.1257-27.119512.4618-26.8173
23.1501-0.9775-0.05475.7345-1.06135.4230.10180.0732-0.1429-0.4865-0.05440.20240.4552-0.0151-0.04480.2317-0.0144-0.03180.18420.0150.1495-24.1662-0.5243-25.7703
37.72923.64530.67428.49511.44472.98140.0739-0.0598-0.5577-0.1798-0.05940.59430.989-0.3962-0.020.24780.0406-0.06380.26350.08220.3291-29.3928-9.1027-17.0167
44.1252-2.0220.07787.1744-2.45723.80290.0795-0.003-0.0293-0.03-0.1165-0.14980.18870.19070.01150.2058-0.0298-0.02280.19360.01980.1548-18.46540.7244-15.7004
54.16120.14990.15955.1393-3.02297.68420.0862-0.6425-0.32570.4726-0.0259-0.53110.0492-0.0264-0.01370.30590.0001-0.08160.25450.00650.2301-19.525315.2709-18.5008
62.49481.0444-1.22096.0067-3.23146.93650.2578-0.1715-0.1150.46450.06520.9333-0.751-0.6288-0.2520.27990.09030.0920.31140.01230.3447-36.275818.5384-20.54
77.7644.7377-0.83478.847-3.58554.76660.6866-1.43150.7011.1536-0.32580.1813-0.0593-0.3347-0.36140.4072-0.043-0.00460.4457-0.04870.2153-19.01221.6908-12.8432
86.60430.05410.69273.28770.04411.05180.03220.0860.189-0.43380.0416-0.30120.0856-0.1981-0.03610.25090.0696-0.00910.27240.0030.0934-21.739222.5094-31.9976
95.10980.56330.33274.86060.45923.8924-0.0069-0.37790.05780.5683-0.2006-0.28320.13830.5220.18550.22270.02290.0280.27570.01810.1431-19.943219.8928-21.451
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 40 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 41 through 76 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 88 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 89 through 127 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 128 through 139 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 140 through 149 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 150 through 160 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 161 through 175 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 176 through 187 )A0

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