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- PDB-8ta1: Crystal Structure of Dihydrofolate reductase (DHFR) from Mycobact... -

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Basic information

Entry
Database: PDB / ID: 8ta1
TitleCrystal Structure of Dihydrofolate reductase (DHFR) from Mycobacterium ulcerans Agy99 in complex with NADP and inhibitor MAM907
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/INHIBITOR / SSGCID / STRUCTURAL GENOMICS / SEATTLE STRUCTURAL GENOMICS CENTER FOR INFECTIOUS DISEASE / Dihydrofolate reductase / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


dihydrofolate metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / cytosol
Similarity search - Function
Dihydrofolate reductase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase-like domain superfamily
Similarity search - Domain/homology
ACETATE ION / : / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium ulcerans (bacteria)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsSeattle Structural Genomics Center for Infectious Disease / Seattle 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)75N93022C00036 United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium , Two Emerging Human Pathogens.
Authors: Andrade Meirelles, M. / Almeida, V.M. / Sullivan, J.R. / de Toledo, I. / Dos Reis, C.V. / Cunha, M.R. / Zigweid, R. / Shim, A. / Sankaran, B. / Woodward, E.L. / Seibold, S. / Liu, L. / Mian, ...Authors: Andrade Meirelles, M. / Almeida, V.M. / Sullivan, J.R. / de Toledo, I. / Dos Reis, C.V. / Cunha, M.R. / Zigweid, R. / Shim, A. / Sankaran, B. / Woodward, E.L. / Seibold, S. / Liu, L. / Mian, M.R. / Battaile, K.P. / Riley, J. / Duncan, C. / Simeons, F.R.C. / Ferguson, L. / Joji, H. / Read, K.D. / Lovell, S. / Staker, B.L. / Behr, M.A. / Pilli, R.A. / Counago, R.M.
History
DepositionJun 26, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)20,6647
Polymers19,0361
Non-polymers1,6286
Water3,819212
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)28.722, 66.265, 44.138
Angle α, β, γ (deg.)90.00, 92.21, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Dihydrofolate reductase


Mass: 19035.619 Da / Num. of mol.: 1 / Fragment: MyulA.01062.a.B13 / Mutation: C89S, E96A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium ulcerans (bacteria) / Strain: Agy99 / Gene: dfrA, MUL_2179 / Plasmid: MyulA.01062.a.B13 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: A0PQG8, dihydrofolate reductase

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Non-polymers , 6 types, 218 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-EII / 3-(2-{3-[(2,4-diamino-6-cyclohexylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid


Mass: 414.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H30N4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: 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
#6: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 212 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 44.22 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.6
Details: Berkeley H8: 30% (w/v) PEG 4000, 100 mM Sodium acetate / Hydrochloric acid pH 4.6, 200 mM Ammonium acetate. Plate 13388 H8 drop 1. MyulA.01062.a.B13.PS38720 at 8.9 mg/mL. 2mM MAM907 and 2mM ...Details: Berkeley H8: 30% (w/v) PEG 4000, 100 mM Sodium acetate / Hydrochloric acid pH 4.6, 200 mM Ammonium acetate. Plate 13388 H8 drop 1. MyulA.01062.a.B13.PS38720 at 8.9 mg/mL. 2mM MAM907 and 2mM NADP added to the protein prior to crystallization. Plate 13388 well H8 drop 1, Cryo: 80% crystallant + 20% PEG 200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: BRUKER D8 QUEST / Wavelength: 1.5418 Å
DetectorType: Bruker PHOTON III / Detector: PIXEL / Date: Jun 21, 2023
RadiationMonochromator: HELIOS MULTILAYER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.5→44.11 Å / Num. obs: 26509 / % possible obs: 100 % / Redundancy: 8.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.037 / Rrim(I) all: 0.109 / Χ2: 0.98 / Net I/σ(I): 18.1 / Num. measured all: 230896
Reflection shellResolution: 1.5→1.53 Å / % possible obs: 100 % / Redundancy: 5.8 % / Rmerge(I) obs: 1.247 / Num. measured all: 7525 / Num. unique obs: 1304 / CC1/2: 0.476 / Rpim(I) all: 0.571 / Rrim(I) all: 1.378 / Χ2: 0.78 / Net I/σ(I) obs: 1.5

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Processing

Software
NameVersionClassification
PHENIX1.21rc1_4933refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→22.27 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.03 / Phase error: 17.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1674 1320 4.99 %
Rwork0.1465 --
obs0.1476 26479 99.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.5→22.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1252 0 100 212 1564
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011415
X-RAY DIFFRACTIONf_angle_d1.1051944
X-RAY DIFFRACTIONf_dihedral_angle_d17.975527
X-RAY DIFFRACTIONf_chiral_restr0.073214
X-RAY DIFFRACTIONf_plane_restr0.013243
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.560.23461310.23992770X-RAY DIFFRACTION100
1.56-1.630.24391360.21182796X-RAY DIFFRACTION100
1.63-1.720.211910.18532853X-RAY DIFFRACTION100
1.72-1.820.22271470.16432785X-RAY DIFFRACTION100
1.82-1.970.16461640.13882751X-RAY DIFFRACTION100
1.97-2.160.15361670.13082785X-RAY DIFFRACTION100
2.16-2.470.1731590.1282790X-RAY DIFFRACTION100
2.48-3.120.14891820.1342774X-RAY DIFFRACTION100
3.12-22.270.14011430.12822855X-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)
12.01380.1349-0.07132.40450.11313.23370.009-0.22640.17480.0785-0.0161-0.08320.02870.01070.00860.0562-0.0004-0.00420.0513-0.01770.08194.7501-6.725716.4343
22.14290.03750.36323.19833.19175.19020.016-0.15690.1976-0.0057-0.25670.2659-0.1631-0.29720.17210.0640.0016-0.00450.0757-0.0240.092-7.5688-5.912713.181
33.1206-0.6227-0.08321.5919-0.03551.8174-0.0502-0.1211-0.06380.08010.02560.05620.0104-0.08490.03020.0627-0.00330.0060.0478-0.00560.0621-3.2415-18.571812.9194
43.7633-0.6567-0.50461.30940.0580.638-0.0660.0459-0.3911-0.13260.0119-0.03850.1613-0.02870.03160.1175-0.01080.01160.0667-0.02120.1311.3093-26.66158.6381
50.30510.0328-0.14624.15991.10423.0866-0.04610.1185-0.0436-0.45680.04090.025-0.0372-0.0384-0.0050.1005-0.0093-0.0010.0908-0.00590.0975-0.3394-19.0440.5749
61.7518-1.2264-0.37631.7520.3571.89430.08350.08010.0244-0.1175-0.1039-0.026-0.11380.0353-0.00060.0439-0.0146-0.00310.04450.00280.05845.473-6.92226.2645
70.9979-1.2983-1.04162.41971.32711.0824-0.2893-0.72360.5860.42780.235-0.5189-0.07050.0379-0.25480.13610.0335-0.05950.1811-0.08240.216113.5559-6.1222.6074
80.409-0.02520.86280.66310.02611.81910.16560.16450.1087-0.0591-0.0565-0.0638-0.32520.23570.15560.14370.0150.05150.10130.05270.10618.67030.17223.4147
91.455-0.276-2.18751.35070.94037.67410.12890.03930.1877-0.0792-0.0373-0.0067-0.148-0.1783-0.04480.09860.01140.00590.0577-0.00270.1036-0.87963.787212.5144
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 26 )
2X-RAY DIFFRACTION2chain 'A' and (resid 27 through 37 )
3X-RAY DIFFRACTION3chain 'A' and (resid 38 through 62 )
4X-RAY DIFFRACTION4chain 'A' and (resid 63 through 78 )
5X-RAY DIFFRACTION5chain 'A' and (resid 79 through 102 )
6X-RAY DIFFRACTION6chain 'A' and (resid 103 through 122 )
7X-RAY DIFFRACTION7chain 'A' and (resid 123 through 132 )
8X-RAY DIFFRACTION8chain 'A' and (resid 133 through 145 )
9X-RAY DIFFRACTION9chain 'A' and (resid 146 through 165 )

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