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- PDB-8f80: Crystal Structure of Dihydrofolate reductase (DHFR) from Mycobact... -

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Basic information

Entry
Database: PDB / ID: 8f80
TitleCrystal Structure of Dihydrofolate reductase (DHFR) from Mycobacterium ulcerans Agy99 in complex with NADP and inhibitor MAM738
ComponentsDihydrofolate reductase
KeywordsOXIDOREDUCTASE/INHIBITOR / SSGCID / STRUCTURAL GENOMICS / SEATTLE STRUCTURAL GENOMICS CENTER FOR INFECTIOUS DISEASE / 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
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Chem-XJB / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium ulcerans (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.1 Å
AuthorsSeattle Structural Genomics Center for Infectious Disease / Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93022C00036 United States
National Institutes of Health/Office of the DirectorS10OD030394 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
DepositionNov 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: diffrn / Item: _diffrn.ambient_temp
Revision 1.2Nov 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 1.3Nov 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

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Assembly

Deposited unit
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,3725
Polymers19,0361
Non-polymers1,3364
Water3,549197
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)29.394, 70.749, 36.216
Angle α, β, γ (deg.)90.00, 111.44, 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) / References: UniProt: A0PQG8, dihydrofolate reductase

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Non-polymers , 5 types, 201 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-XJB / 3-[2-(3-{[2,4-diamino-6-(4-methoxyphenyl)pyrimidin-5-yl]oxy}propoxy)phenyl]propanoic acid


Mass: 438.476 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N4O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 1.84 Å3/Da / Density % sol: 33.2 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus D3: 20%(v/v) Glycerol, 10% w/v PEG 4000, 100 mM Imidazole/MES, pH 6.5, 20 mM 1,6-Hexanediol, 20 mM 1-Butanol, 20 mM 1,2-Propanediol, 20 mM 2-Propanol, 20 mM 1,4-Butanediol and 20 mM ...Details: Morpheus D3: 20%(v/v) Glycerol, 10% w/v PEG 4000, 100 mM Imidazole/MES, pH 6.5, 20 mM 1,6-Hexanediol, 20 mM 1-Butanol, 20 mM 1,2-Propanediol, 20 mM 2-Propanol, 20 mM 1,4-Butanediol and 20 mM 1,3-Propanediol, MyulA.01062.a.B13.PS38558 at 10 mg/mL. Tray: Tray 355D3/ MAM738 +NADP, Puck: CPS5110_06, Cryo: Direct

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 19-ID / Wavelength: 0.97949 Å
DetectorType: DECTRIS EIGER2 XE 9M / Detector: PIXEL / Date: Oct 30, 2022
RadiationMonochromator: Double Crystal Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.1→70.75 Å / Num. obs: 53850 / % possible obs: 96.6 % / Redundancy: 6.6 % / CC1/2: 1 / Rmerge(I) obs: 0.032 / Rpim(I) all: 0.013 / Rrim(I) all: 0.034 / Χ2: 1.01 / Net I/σ(I): 25.7 / Num. measured all: 355439
Reflection shellResolution: 1.1→1.13 Å / % possible obs: 79.6 % / Redundancy: 4.4 % / Rmerge(I) obs: 0.213 / Num. measured all: 14673 / Num. unique obs: 3300 / CC1/2: 0.958 / Rpim(I) all: 0.112 / Rrim(I) all: 0.242 / Χ2: 1.06 / Net I/σ(I) obs: 5.8

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.1→21.64 Å / SU ML: 0.06 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 12.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1328 2608 4.85 %
Rwork0.1176 --
obs0.1184 53764 96.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.1→21.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1252 0 90 197 1539
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081507
X-RAY DIFFRACTIONf_angle_d1.1422079
X-RAY DIFFRACTIONf_dihedral_angle_d12.446617
X-RAY DIFFRACTIONf_chiral_restr0.078224
X-RAY DIFFRACTIONf_plane_restr0.014266
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1-1.120.15291080.12932133X-RAY DIFFRACTION77
1.12-1.140.14171260.11652476X-RAY DIFFRACTION88
1.14-1.160.14311290.10722631X-RAY DIFFRACTION94
1.16-1.190.1281280.10482681X-RAY DIFFRACTION96
1.19-1.220.13381570.10482665X-RAY DIFFRACTION97
1.22-1.250.13491410.10332702X-RAY DIFFRACTION97
1.25-1.280.12941240.10162743X-RAY DIFFRACTION97
1.28-1.320.13821040.10162707X-RAY DIFFRACTION97
1.32-1.360.13751520.10742708X-RAY DIFFRACTION98
1.36-1.410.13191430.10862762X-RAY DIFFRACTION98
1.41-1.470.12391270.10752756X-RAY DIFFRACTION98
1.47-1.530.13081530.10432724X-RAY DIFFRACTION98
1.53-1.620.11541590.10072747X-RAY DIFFRACTION99
1.62-1.720.1321330.1082790X-RAY DIFFRACTION99
1.72-1.850.1261580.11532751X-RAY DIFFRACTION99
1.85-2.030.11121280.11252807X-RAY DIFFRACTION100
2.03-2.330.13021180.11582831X-RAY DIFFRACTION100
2.33-2.930.14681560.132718X-RAY DIFFRACTION97
2.93-21.640.13691640.13272824X-RAY DIFFRACTION100

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