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- PDB-6vs5: Mycobacterium tuberculosis dihydrofolate reductase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 6vs5
TitleMycobacterium tuberculosis dihydrofolate reductase in complex with 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (fragment 1)
ComponentsDihydrofolate reductase
KeywordsBIOSYNTHETIC PROTEIN / folate pathway
Function / homology
Function and homology information


dihydrofolate metabolic process / NADP+ binding / folic acid metabolic process / glycine biosynthetic 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 domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
5-methyl-1-phenyl-pyrazole-4-carboxylic acid / : / Chem-NDP / PHOSPHATE ION / Dihydrofolate reductase / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.758 Å
AuthorsRibeiro, J.A. / Tyrakis, P. / Blundell, T. / 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 10, 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)38,48913
Polymers35,7872
Non-polymers2,70211
Water5,242291
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,2927
Polymers17,8931
Non-polymers1,3996
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,1976
Polymers17,8931
Non-polymers1,3045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4960 Å2
ΔGint-41 kcal/mol
Surface area14460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.477, 70.453, 71.876
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 (bacteria)
Gene: folA, ERS023446_01268, ERS027651_02380, SAMEA2682864_02011, SAMEA2683035_01637
Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: A0A0E8UVJ4, UniProt: P9WNX1*PLUS, dihydrofolate reductase

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Non-polymers , 5 types, 302 molecules

#2: Chemical ChemComp-CO / COBALT (II) ION


Mass: 58.933 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Co
#3: Chemical
ChemComp-9FH / 5-methyl-1-phenyl-pyrazole-4-carboxylic acid


Mass: 202.209 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H10N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#5: Chemical ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 291 / 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: 2.17 Å3/Da / Density % sol: 43.44 %
Crystal growTemperature: 293 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: D03B-MX1 / Wavelength: 1.45868 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: 1.45868 Å / Relative weight: 1
Reflection twinOperator: -h,l,k / Fraction: 0.11
ReflectionResolution: 1.7→46.72 Å / Num. obs: 31632 / % possible obs: 99.6 % / Redundancy: 11.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.026 / Rrim(I) all: 0.092 / Net I/σ(I): 19
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
1.76-1.798.60.9511422016520.7160.3371.0122.293.8
8.96-46.72100.04729292940.9980.0150.0549.999.6

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Processing

Software
NameVersionClassification
Aimless0.5.27data scaling
PHENIX1.14refinement
PDB_EXTRACT3.25data extraction
SADABSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1DF7

1df7


Resolution: 1.758→35.227 Å / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 26.37
RfactorNum. reflection% reflection
Rfree0.2556 1632 5.2 %
Rwork0.2003 --
obs0.2029 31369 98.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 82.42 Å2 / Biso mean: 28.4649 Å2 / Biso min: 12.06 Å2
Refinement stepCycle: final / Resolution: 1.758→35.227 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2480 0 173 291 2944
Biso mean--25.61 37.54 -
Num. residues----318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082727
X-RAY DIFFRACTIONf_angle_d1.1243734
X-RAY DIFFRACTIONf_chiral_restr0.058388
X-RAY DIFFRACTIONf_plane_restr0.007474
X-RAY DIFFRACTIONf_dihedral_angle_d17.9921522
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7592-1.8160.32721590.3011259192
1.816-1.88090.33191500.2801266394
1.8809-1.95620.31161170.2648271095
1.9562-2.04520.26451400.2677269195
2.0452-2.1530.28351400.2517269195
2.153-2.28790.30021510.2353270394
2.2879-2.46450.27831610.2299268394
2.4645-2.71240.25291340.2138267694
2.7124-3.10470.24411220.1893272394
3.1047-3.91080.21781500.158274194
3.9108-350.23091770.1528286694
Refinement TLS params.Method: refined / Origin x: 22.9058 Å / Origin y: 0.2709 Å / Origin z: 17.9497 Å
111213212223313233
T0.1652 Å2-0.012 Å2-0.0266 Å2-0.1385 Å2-0.0252 Å2--0.1523 Å2
L1.2968 °2-0.4956 °2-0.3171 °2-0.5036 °2-0.1282 °2--0.2745 °2
S0.0063 Å °0.0125 Å °0.0439 Å °0.0052 Å °-0.013 Å °-0.0666 Å °-0.001 Å °0.0187 Å °-0.0017 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 159
2X-RAY DIFFRACTION1allB1 - 159
3X-RAY DIFFRACTION1allC1 - 2
4X-RAY DIFFRACTION1allD1 - 3
5X-RAY DIFFRACTION1allD4
6X-RAY DIFFRACTION1allF1 - 2
7X-RAY DIFFRACTION1allS1 - 292
8X-RAY DIFFRACTION1allS293 - 298
9X-RAY DIFFRACTION1allE1 - 3

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