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- PDB-8cq9: Mycobacterium tuberculosis dihydrofolate reductase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 8cq9
TitleMycobacterium tuberculosis dihydrofolate reductase in complex with 5-(cyclopropylethynyl)-6-(4-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine
ComponentsDihydrofolate reductase
KeywordsBIOSYNTHETIC PROTEIN / Dihydrofolate reductase Mycobacterium tuberculosis
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
: / Chem-NDP / : / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsKirkman, T.J. / Dias, M.V.B. / Coyne, A.G.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
UK Research and Innovation (UKRI) United Kingdom
CitationJournal: To Be Published
Title: Expansion of a series of pyrimidine derivatives utilising fragment-based merging leads to increased affinity to Mycobacterium tuberculosis dihydrofolate reductase (unpublished currently)
Authors: Kirkman, T.J. / Dias, M.V.B. / Coyne, A.G.
History
DepositionMar 4, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Dihydrofolate reductase
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,61513
Polymers35,7872
Non-polymers2,82911
Water4,594255
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5640 Å2
ΔGint-65 kcal/mol
Surface area14950 Å2
Unit cell
Length a, b, c (Å)61.658, 71.068, 72.430
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Dihydrofolate reductase


Mass: 17893.293 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: folA / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0A0E8UVJ4

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Non-polymers , 6 types, 266 molecules

#2: Chemical ChemComp-VFU / 5-[(~{E})-2-cyclopropylethenyl]-6-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine


Mass: 320.312 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15F3N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Co
#5: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 255 / 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: 2.22 Å3/Da / Density % sol: 44.52 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: 1.6M ammonium sulphate, 100 mM MES, 10 mM CoCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 14, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.75→46.95 Å / Num. obs: 32762 / % possible obs: 99.8 % / Redundancy: 12.1 % / CC1/2: 0.997 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.042 / Rrim(I) all: 0.147 / Χ2: 1.02 / Net I/σ(I): 12.8 / Num. measured all: 394870
Reflection shellResolution: 1.75→1.78 Å / % possible obs: 95.9 % / Redundancy: 8.7 % / Rmerge(I) obs: 1.092 / Num. measured all: 14871 / Num. unique obs: 1718 / CC1/2: 0.734 / Rpim(I) all: 0.387 / Rrim(I) all: 1.162 / Χ2: 0.76 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2_refinement
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→36.22 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2276 1600 4.89 %
Rwork0.1987 --
obs0.2001 32690 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.75→36.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2488 0 167 255 2910
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092722
X-RAY DIFFRACTIONf_angle_d1.3523726
X-RAY DIFFRACTIONf_dihedral_angle_d30.065397
X-RAY DIFFRACTIONf_chiral_restr0.075386
X-RAY DIFFRACTIONf_plane_restr0.009469
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.810.29291390.23212734X-RAY DIFFRACTION97
1.81-1.870.25411590.22322757X-RAY DIFFRACTION100
1.87-1.950.25951410.21412819X-RAY DIFFRACTION100
1.95-2.030.23561370.20992789X-RAY DIFFRACTION100
2.03-2.140.26031560.20832787X-RAY DIFFRACTION100
2.14-2.280.21411230.20062841X-RAY DIFFRACTION100
2.28-2.450.2581330.20652830X-RAY DIFFRACTION100
2.45-2.70.23741430.21212832X-RAY DIFFRACTION100
2.7-3.090.2177960.21092900X-RAY DIFFRACTION100
3.09-3.890.2231780.18452839X-RAY DIFFRACTION100
3.89-36.220.20281950.17992962X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 23.1907 Å / Origin y: 0.2436 Å / Origin z: 17.8427 Å
111213212223313233
T0.1738 Å2-0.0028 Å2-0.0223 Å2-0.1558 Å2-0.0046 Å2--0.1467 Å2
L1.2483 °2-0.2416 °2-0.4973 °2-0.4423 °20.0446 °2--0.2562 °2
S-0.0076 Å °-0.0138 Å °-0.0062 Å °-0.0038 Å °0.0039 Å °-0.0449 Å °0.0248 Å °0.0181 Å °0.0073 Å °
Refinement TLS groupSelection details: all

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