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- PDB-5sd6: Crystal Structure of Dihydrofolate Reductase from Homo sapiens bo... -

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Basic information

Entry
Database: PDB / ID: 5sd6
TitleCrystal Structure of Dihydrofolate Reductase from Homo sapiens bound to NADP and SDDC Inhibitor SDDC-892
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 / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / 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-HXV / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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-892
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

Downloads & links

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,14111
Polymers21,4811
Non-polymers1,66110
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.190, 74.190, 143.210
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-314-

HOH

21A-404-

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 (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 6 types, 137 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-HXV / 6-ethyl-5-(4-{2-[2-(1H-tetrazol-5-yl)ethyl]phenoxy}butoxy)pyrimidine-2,4-diamine


Mass: 398.462 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H26N8O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 4.59 Å3/Da / Density % sol: 73.18 % / Mosaicity: 0.17 °
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop
Details: MCSG2 E5 (273901e5): 200mM Lithium sulfate, 100mM Sodium acetate:Acetic acid pH4.5, 20% (w/v) PEG8000; prot conc 26mg/mL, cryo 20% EG, puck ogi6-6

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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: C 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 22057 / % possible obs: 98 % / Observed criterion σ(I): -3 / Biso Wilson estimate: 41.46 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.066 / Rrim(I) all: 0.07 / Net I/σ(I): 22.11 / Num. measured all: 170145
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
2.15-2.210.8740.5973.1912386160315900.63499.2
2.21-2.270.9370.4823.8812340159715820.51299.1
2.27-2.330.9430.3724.9711907155215380.39599.1
2.33-2.40.9580.3275.7711643150414910.34699.1
2.4-2.480.9780.2856.5111153144814320.30298.9
2.48-2.570.9780.2268.2710910141313960.23998.8
2.57-2.670.9850.18710.310440136613470.19898.6
2.67-2.780.9910.15312.2810226132613070.16298.6
2.78-2.90.9960.11216.279599125412330.11898.3
2.9-3.040.9970.08920.079390122711960.09497.5
3.04-3.210.9980.0725.318686115311210.07497.2
3.21-3.40.9990.05432.288390111310880.05797.8
3.4-3.630.9990.0442.887813103110110.04298.1
3.63-3.930.9990.03647.1173469869590.03897.3
3.93-4.30.9990.03153.8267108988800.03398
4.3-4.810.9990.02957.0960078308040.0396.9
4.81-5.550.9990.02756.8153547357110.02996.7
5.55-6.80.9990.02753.245196346090.02996.1
6.8-9.6210.02261.2435185124850.02394.7
9.6210.0263.5318083142770.02188.2

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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: 2.15→40.144 Å / Occupancy max: 1 / Occupancy min: 0 / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.26 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2044 1986 9.01 %
Rwork0.167 20067 -
obs0.1705 22053 98.05 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 118.48 Å2 / Biso mean: 38.7809 Å2 / Biso min: 17.39 Å2
Refinement stepCycle: LAST / Resolution: 2.15→40.144 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1482 0 103 127 1712
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071683
X-RAY DIFFRACTIONf_angle_d0.9462296
X-RAY DIFFRACTIONf_chiral_restr0.061243
X-RAY DIFFRACTIONf_plane_restr0.005286
X-RAY DIFFRACTIONf_dihedral_angle_d9.6321702
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.1501-2.20380.28351370.22981388152599
2.2038-2.26340.27071320.20411433156599
2.2634-2.330.2311260.19091446157299
2.33-2.40520.22651180.18831442156099
2.4052-2.49120.221430.18821410155399
2.4912-2.59090.2441300.19071428155899
2.5909-2.70880.25791540.1851411156599
2.7088-2.85150.20991550.18131413156898
2.8515-3.03010.22511490.17941403155298
3.0301-3.2640.22491410.17841439158098
3.264-3.59230.17781330.15621445157898
3.5923-4.11170.18741500.13631442159297
4.1117-5.17850.16481580.1341455161398
5.1785-40.15140.20071600.18111512167294
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)
17.745-0.07981.57154.7449-1.01046.1780.0685-0.1506-0.41940.08910.0840.377-0.1418-0.2557-0.10990.1816-0.00310.03870.20950.01870.2206-30.32114.3987-22.0108
23.2157-2.06894.07813.9089-3.27266.6319-0.1636-0.0352-0.1117-0.52340.0569-0.07130.2629-0.03620.15610.2683-0.0390.0150.28060.02280.2084-22.832611.1878-32.7188
35.8776-1.7012-0.55665.7438-0.6986.81110.13580.2289-0.2633-0.36210.00830.12430.4021-0.1609-0.12830.2501-0.0222-0.03990.1495-0.00410.1688-24.5933-0.0018-25.5547
46.87243.36464.53962.78754.61549.03520.2818-0.0294-0.4411-0.0284-0.05180.4260.7719-0.362-0.1840.31960.0273-0.01970.28730.11250.331-29.3474-8.0014-16.1712
55.3777-2.2470.94068.1306-3.41244.4996-0.0517-0.133-0.0520.104-0.0304-0.38410.06090.26080.06670.2034-0.0312-0.02160.25130.00650.1986-18.27531.3198-15.7284
63.8782-4.16334.33935.4853-2.69488.93220.4435-0.6915-0.63720.16710.011-0.09830.2982-0.0957-0.50190.3325-0.0753-0.08270.31650.05610.384-18.997815.5468-17.9682
77.56283.7579-2.9413.8374-3.35373.52060.3589-0.40890.42540.61490.09330.8271-0.5862-0.3811-0.46810.41090.12180.09360.4079-0.0450.3714-35.829318.8248-19.8663
84.28391.92512.034.66760.88893.93110.1594-0.36240.16440.23040.00990.0853-0.0821-0.2872-0.17320.23920.04530.00340.2243-0.00950.1993-20.764322.4401-23.6684
99.3287-0.94034.87018.2694-1.2558.49850.0978-0.19750.15290.506-0.034-0.3587-0.03560.5053-0.0070.2079-0.01310.04930.2530.00140.2083-20.32520.4623-21.9109
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 28 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 29 through 40 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 41 through 76 )A0
4X-RAY DIFFRACTION4chain 'A' and (resid 77 through 88 )A0
5X-RAY DIFFRACTION5chain 'A' and (resid 89 through 127 )A0
6X-RAY DIFFRACTION6chain 'A' and (resid 128 through 139 )A0
7X-RAY DIFFRACTION7chain 'A' and (resid 140 through 149 )A0
8X-RAY DIFFRACTION8chain 'A' and (resid 150 through 175 )A0
9X-RAY DIFFRACTION9chain 'A' and (resid 176 through 187 )A0

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