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- PDB-6vsd: Mycobacterium tuberculosis dihydrofolate reductase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 6vsd
TitleMycobacterium tuberculosis dihydrofolate reductase in complex with 3-((thiophen-2-ylthio)methyl)benzoic acid (fragment 13)
ComponentsDihydrofolate reductase
KeywordsBIOSYNTHETIC PROTEIN / folate pathway
Function / homology
Function and homology information


NADP+ binding / dihydrofolate metabolic process / folic acid metabolic process / dihydrofolate reductase / dihydrofolate reductase activity / tetrahydrofolate biosynthetic process / one-carbon metabolic process / NADP binding / cytosol
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / 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 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
: / 3-(thiophen-2-ylsulfanylmethyl)benzoic acid / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / PHOSPHATE ION / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.693 Å
AuthorsRibeiro, J.A. / Dias, M.V.B.
Funding support Brazil, 1items
OrganizationGrant numberCountry
Sao Paulo Research Foundation (FAPESP)2018/00351-1 Brazil
CitationJournal: Acs Infect Dis. / Year: 2020
Title: Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase fromMycobacterium tuberculosis.
Authors: Ribeiro, J.A. / Hammer, A. / Libreros-Zuniga, G.A. / Chavez-Pacheco, S.M. / Tyrakis, P. / de Oliveira, G.S. / Kirkman, T. / El Bakali, J. / Rocco, S.A. / Sforca, M.L. / Parise-Filho, R. / ...Authors: Ribeiro, J.A. / Hammer, A. / Libreros-Zuniga, G.A. / Chavez-Pacheco, S.M. / Tyrakis, P. / de Oliveira, G.S. / Kirkman, T. / El Bakali, J. / Rocco, S.A. / Sforca, M.L. / Parise-Filho, R. / Coyne, A.G. / Blundell, T.L. / Abell, C. / Dias, M.V.B.
History
DepositionFeb 11, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 26, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)38,08310
Polymers35,7872
Non-polymers2,2968
Water5,585310
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0425
Polymers17,8931
Non-polymers1,1494
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0415
Polymers17,8931
Non-polymers1,1484
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4760 Å2
ΔGint-46 kcal/mol
Surface area15250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.745, 71.171, 71.798
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 (strain ATCC 25618 / H37Rv) (bacteria)
Strain: ATCC 25618 / H37Rv / Gene: folA, dfrA, Rv2763c, MTV002.28c / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P9WNX1, dihydrofolate reductase

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Non-polymers , 6 types, 318 molecules

#2: Chemical ChemComp-JBB / 3-(thiophen-2-ylsulfanylmethyl)benzoic acid


Mass: 250.337 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H10O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NAP / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / 2'-MONOPHOSPHOADENOSINE 5'-DIPHOSPHORIBOSE


Mass: 743.405 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H28N7O17P3
#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.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 44.2 %
Crystal growTemperature: 297 K / Method: vapor diffusion, hanging drop
Details: 1.6 M ammonium sulfate, 100 mM MES (2-(N-morpholino) ethanesulfonic acid), pH 6.5, 10 mM CoCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: LNLS / Beamline: W01B-MX2 / Wavelength: 1.48 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Mar 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.48 Å / Relative weight: 1
Reflection twinOperator: -h,l,k / Fraction: 0.32
ReflectionResolution: 1.69→46.81 Å / Num. obs: 35767 / % possible obs: 99.4 % / Redundancy: 11.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.073 / Rpim(I) all: 0.022 / Rrim(I) all: 0.076 / Net I/σ(I): 21 / Num. measured all: 409192
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.69-1.727.40.9571214016500.690.3661.0281.888.3
8.96-46.8110.40.04730432940.9990.0150.0545.199.6

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
PHENIX1.14refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1df7

1df7


Resolution: 1.693→46.639 Å / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 27.45
RfactorNum. reflection% reflection
Rfree0.2096 1844 5.16 %
Rwork0.1709 --
obs0.1745 35710 99.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 82.98 Å2 / Biso mean: 27.0975 Å2 / Biso min: 12.68 Å2
Refinement stepCycle: final / Resolution: 1.693→46.639 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2484 0 140 310 2934
Biso mean--27.79 37.08 -
Num. residues----318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072692
X-RAY DIFFRACTIONf_angle_d1.0153679
X-RAY DIFFRACTIONf_chiral_restr0.054386
X-RAY DIFFRACTIONf_plane_restr0.006467
X-RAY DIFFRACTIONf_dihedral_angle_d19.0461519
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6957-1.74150.3811350.3842501263692
1.7415-1.79270.35771420.2982550269295
1.7927-1.85050.27561440.26722581272595
1.8505-1.91660.28921470.24692537268495
1.9166-1.99320.25441450.24062590273595
1.9932-2.08380.2751510.23592557270894
2.0838-2.19350.22711460.21522597274395
2.1935-2.33070.24681170.20572593271096
2.3307-2.51020.24251120.19232626273896
2.5102-2.76190.23431150.17832654276996
2.7619-3.15970.19751680.15582600276894
3.1597-3.97360.1861480.12282662281095
3.9736-17.85630.14841620.11532754291694
Refinement TLS params.Method: refined / Origin x: 22.8678 Å / Origin y: 0.331 Å / Origin z: 17.779 Å
111213212223313233
T0.1545 Å2-0.0014 Å2-0.0196 Å2-0.1439 Å2-0.0182 Å2--0.1845 Å2
L0.7446 °2-0.326 °2-0.135 °2-0.3038 °2-0.0923 °2--0.1422 °2
S0.0024 Å °-0.0024 Å °0.0338 Å °-0.011 Å °-0.0177 Å °-0.0451 Å °-0.0061 Å °0.013 Å °0.0146 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 159
2X-RAY DIFFRACTION1allB1 - 159
3X-RAY DIFFRACTION1allC2
4X-RAY DIFFRACTION1allC3
5X-RAY DIFFRACTION1allD1 - 2
6X-RAY DIFFRACTION1allE1 - 2
7X-RAY DIFFRACTION1allS1 - 303
8X-RAY DIFFRACTION1allS304 - 326
9X-RAY DIFFRACTION1allS327 - 334
10X-RAY DIFFRACTION1allF2
11X-RAY DIFFRACTION1allG1

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