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- PDB-6vs8: Mycobacterium tuberculosis dihydrofolate reductase in complex wit... -

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Basic information

Entry
Database: PDB / ID: 6vs8
TitleMycobacterium tuberculosis dihydrofolate reductase in complex with ethyl 2-methyl thiazole-4-carboxylate(fragment 3)
ComponentsDihydrofolate reductase
KeywordsBIOSYNTHETIC PROTEIN / folate pathway
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 / NADP binding / cytosol
Similarity search - Function
Dihydrofolate reductase / Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / 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
: / NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / PHOSPHATE ION / ethyl 2-methyl-1,3-thiazole-4-carboxylate / Dihydrofolate reductase / Dihydrofolate reductase
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.829 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 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)38,40315
Polymers35,7872
Non-polymers2,61613
Water6,071337
1
A: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,0586
Polymers17,8931
Non-polymers1,1655
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Dihydrofolate reductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,3459
Polymers17,8931
Non-polymers1,4528
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5810 Å2
ΔGint-87 kcal/mol
Surface area14970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.278, 70.779, 72.108
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(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: A0A0E8UVJ4, UniProt: P9WNX1*PLUS, dihydrofolate reductase

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Non-polymers , 6 types, 350 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-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-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-RJY / ethyl 2-methyl-1,3-thiazole-4-carboxylate


Mass: 171.217 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H9NO2S / Feature type: SUBJECT OF INVESTIGATION
#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.: 337 / 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: 2.15 Å3/Da / Density % sol: 42.77 %
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: D03B-MX1 / Wavelength: 1.4 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: 1.4 Å / Relative weight: 1
ReflectionResolution: 1.828→46.25 Å / Num. obs: 27792 / % possible obs: 99.4 % / Redundancy: 11.8 % / Biso Wilson estimate: 21.34 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.119 / Rpim(I) all: 0.036 / Rrim(I) all: 0.125 / Net I/σ(I): 19.1
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
1.83-1.8791.1611409915710.6540.3961.2312.292.3
8.96-46.259.50.04327402890.9990.0140.04556.199.3

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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: 1.829→30.942 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.06
RfactorNum. reflection% reflection
Rfree0.2212 1463 5.28 %
Rwork0.1697 --
obs0.1724 27729 99.38 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 90.96 Å2 / Biso mean: 26.9847 Å2 / Biso min: 11.41 Å2
Refinement stepCycle: final / Resolution: 1.829→30.942 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2482 0 155 337 2974
Biso mean--37.49 36.81 -
Num. residues----318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082709
X-RAY DIFFRACTIONf_angle_d1.0643709
X-RAY DIFFRACTIONf_chiral_restr0.058390
X-RAY DIFFRACTIONf_plane_restr0.007467
X-RAY DIFFRACTIONf_dihedral_angle_d17.3741527
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.829-1.89440.27211590.2456244995
1.8944-1.97020.27511200.20032612100
1.9702-2.05980.24521360.1932614100
2.0598-2.16840.23541500.18492593100
2.1684-2.30420.20691480.17452619100
2.3042-2.48210.19981690.16562585100
2.4821-2.73170.22691460.16962654100
2.7317-3.12670.2451340.16572648100
3.1267-3.9380.20641340.14952701100
3.938-30.940.20651670.16312791100
Refinement TLS params.Method: refined / Origin x: 22.3488 Å / Origin y: 0.0817 Å / Origin z: 17.8787 Å
111213212223313233
T0.156 Å2-0.0125 Å2-0.0208 Å2-0.1424 Å2-0.0072 Å2--0.1385 Å2
L0.7783 °2-0.3478 °2-0.3896 °2-0.3303 °20.0762 °2--0.3124 °2
S-0.0106 Å °-0.0094 Å °0.0131 Å °-0.0223 Å °0.0069 Å °-0.0262 Å °-0.0168 Å °0.0195 Å °0.0001 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1 - 159
2X-RAY DIFFRACTION1allB1 - 159
3X-RAY DIFFRACTION1allD1 - 2
4X-RAY DIFFRACTION1allE1 - 2
5X-RAY DIFFRACTION1allS1 - 328
6X-RAY DIFFRACTION1allS329 - 335
7X-RAY DIFFRACTION1allS336 - 339
8X-RAY DIFFRACTION1allS340 - 341
9X-RAY DIFFRACTION1allF1 - 3
10X-RAY DIFFRACTION1allC1 - 2
11X-RAY DIFFRACTION1allG2 - 5

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