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- PDB-8cq8: Mycobacterium tuberculosis dihydrofolate reductase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 8cq8
TitleMycobacterium tuberculosis dihydrofolate reductase in complex with methyl 4-(2,6-diamino-5-(cyclopropylethynyl)pyrimidin-4-yl)benzoate
ComponentsDihydrofolate reductase
KeywordsBIOSYNTHETIC PROTEIN / Dihydrofolate reductase Mycobacterium tuberculosis
Function / homology
Function and homology information


NADP+ binding / dihydrofolate metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / tetrahydrofolate biosynthetic process / one-carbon metabolic process / 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: 1.8 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utilising fragment-based merging leads to increased affinity to Mycobacterium tuberculosis dihydrofolate reductase (unpublished currently)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)38,98215
Polymers35,7872
Non-polymers3,19513
Water2,252125
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6520 Å2
ΔGint-46 kcal/mol
Surface area14520 Å2
Unit cell
Length a, b, c (Å)60.900, 71.453, 72.260
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, 138 molecules

#2: Chemical ChemComp-VFF / methyl 4-[2,6-bis(azanyl)-5-(2-cyclopropylethynyl)pyrimidin-4-yl]benzoate


Mass: 308.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H16N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: 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
#5: Chemical ChemComp-CO / COBALT (II) ION


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


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.2 Å3/Da / Density % sol: 44 %
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 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→46.57 Å / Num. obs: 29939 / % possible obs: 100 % / Redundancy: 12.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.024 / Rrim(I) all: 0.083 / Χ2: 1 / Net I/σ(I): 18.8 / Num. measured all: 370504
Reflection shellResolution: 1.8→1.84 Å / % possible obs: 100 % / Redundancy: 12.6 % / Rmerge(I) obs: 1.004 / Num. measured all: 21825 / Num. unique obs: 1737 / CC1/2: 0.843 / Rpim(I) all: 0.294 / Rrim(I) all: 1.047 / Χ2: 0.84 / Net I/σ(I) obs: 2.6

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.18.2_3874refinement
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→46.57 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 31.03 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2402 1496 5.01 %
Rwork0.2095 --
obs0.2195 29866 99.91 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.8→46.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2488 0 200 125 2813
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012756
X-RAY DIFFRACTIONf_angle_d1.6673770
X-RAY DIFFRACTIONf_dihedral_angle_d24.705417
X-RAY DIFFRACTIONf_chiral_restr0.139386
X-RAY DIFFRACTIONf_plane_restr0.008472
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.860.39121280.35292544X-RAY DIFFRACTION95
1.86-1.920.37481320.33532534X-RAY DIFFRACTION95
1.92-20.3651130.31992573X-RAY DIFFRACTION96
2-2.090.33351510.31232532X-RAY DIFFRACTION94
2.09-2.20.2841300.29132558X-RAY DIFFRACTION95
2.2-2.340.33921700.28522509X-RAY DIFFRACTION94
2.34-2.520.29271280.27922573X-RAY DIFFRACTION95
2.52-2.780.27831010.25642622X-RAY DIFFRACTION96
2.78-3.180.26631570.23432568X-RAY DIFFRACTION94
3.18-40.2181240.17172636X-RAY DIFFRACTION95
4-46.570.1921590.14042724X-RAY DIFFRACTION94

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