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- PDB-6cml: Trypanosoma brucei methionyl-tRNA synthetase in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 6cml
TitleTrypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor (Chem 2093)
ComponentsMethionyl-tRNA synthetase
Keywordsligase/ligase inhibitor / synthetase / ligase / methionine / inhibitor / Ligase-Ligase Inhibitor complex
Function / homology
Function and homology information


methionine-tRNA ligase / methionine-tRNA ligase activity / methionyl-tRNA aminoacylation / ciliary plasm / mitochondrion / ATP binding / cytoplasm
Similarity search - Function
Methionyl-trna Synthetase; domain 2 / Methionyl-trna Synthetase; domain 2 - #10 / Methionine-tRNA synthetase, type 2 / Anticodon binding domain of methionyl tRNA ligase / Methionyl-tRNA synthetase / Methioninyl-tRNA synthetase core domain / Methionyl-tRNA synthetase, anticodon-binding domain / Isoleucyl-tRNA Synthetase; Domain 1 / Isoleucyl-tRNA Synthetase; Domain 1 / Methionyl/Leucyl tRNA synthetase ...Methionyl-trna Synthetase; domain 2 / Methionyl-trna Synthetase; domain 2 - #10 / Methionine-tRNA synthetase, type 2 / Anticodon binding domain of methionyl tRNA ligase / Methionyl-tRNA synthetase / Methioninyl-tRNA synthetase core domain / Methionyl-tRNA synthetase, anticodon-binding domain / Isoleucyl-tRNA Synthetase; Domain 1 / Isoleucyl-tRNA Synthetase; Domain 1 / Methionyl/Leucyl tRNA synthetase / tRNA synthetases class I (M) / Aminoacyl-tRNA synthetase, class Ia, anticodon-binding / HUPs / Rossmann-like alpha/beta/alpha sandwich fold / Beta Complex / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-96S / METHIONINE / methionine--tRNA ligase
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsBarros-Alvarez, X. / Hol, W.G.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI084004 United States
CitationJournal: Rsc Med Chem / Year: 2020
Title: Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei
Authors: Zhang, Z. / Barros-Alvarez, X. / Gillespie, J.R. / Ranade, R.M. / Huang, W. / Shibata, S. / Molasky, N.M.R. / Faghih, O. / Mushtaq, A. / Choy, R.K.M. / de Hostos, E. / Hol, W.G.J. / ...Authors: Zhang, Z. / Barros-Alvarez, X. / Gillespie, J.R. / Ranade, R.M. / Huang, W. / Shibata, S. / Molasky, N.M.R. / Faghih, O. / Mushtaq, A. / Choy, R.K.M. / de Hostos, E. / Hol, W.G.J. / Verlinde, C.L.M.J. / Buckner, F.S. / Fan, E.
History
DepositionMar 5, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Database references / Category: pdbx_audit_support / struct_ref_seq_dif
Item: _pdbx_audit_support.funding_organization / _struct_ref_seq_dif.details
Revision 1.2Sep 23, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Methionyl-tRNA synthetase
B: Methionyl-tRNA synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,3355
Polymers122,6612
Non-polymers6743
Water2,468137
1
A: Methionyl-tRNA synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,4802
Polymers61,3311
Non-polymers1491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Methionyl-tRNA synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8553
Polymers61,3311
Non-polymers5242
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.640, 106.230, 208.280
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: VAL / Beg label comp-ID: VAL / End auth comp-ID: SER / End label comp-ID: SER / Refine code: _ / Auth seq-ID: 238 - 766 / Label seq-ID: 7 - 535

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

#1: Protein Methionyl-tRNA synthetase


Mass: 61330.715 Da / Num. of mol.: 2 / Mutation: A309T, K452T, K453A, E454A, A499V, S503N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei brucei (eukaryote) / Strain: 927/4 GUTat10.1 / Gene: Tb10.70.6470 / Production host: Escherichia coli (E. coli) / References: UniProt: Q38C91, methionine-tRNA ligase
#2: Chemical ChemComp-MET / METHIONINE


Type: L-peptide linking / Mass: 149.211 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H11NO2S
#3: Chemical ChemComp-96S / 1-[(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-[(2-chloro-4-methoxyphenyl)methyl]-3-ethyl-1,3-dihydro-2H-imidazol-2-one


Mass: 432.303 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19Cl2N5O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O

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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: 3.95 Å3/Da / Density % sol: 68.88 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 1.8-2.1 M AMMONIUM SULFATE, 0.2 M SODIUM CHLORIDE, 0.1 M SODIUM CACODYLATE, PH 6.2-6.8, VAPOR DIFFUSION, SITTING DROP, TEMPERATURE 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 2, 2016
RadiationMonochromator: LIQUID NITROGEN-COOLED DOUBLE CRYSTAL SI(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.7→104.14 Å / Num. obs: 54250 / % possible obs: 100 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.2 / Net I/σ(I): 6.8

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Processing

Software
NameVersionClassification
Aimlessdata reduction
HKL-2000data scaling
PHASERphasing
REFMAC5.8.0135refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.7→104.14 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.925 / Cross valid method: THROUGHOUT / ESU R: 0.387 / ESU R Free: 0.257 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.231 2681 4.9 %RANDOM
Rwork0.204 ---
obs0.205 51494 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 55.58 Å2
Baniso -1Baniso -2Baniso -3
1-8.06 Å20 Å20 Å2
2---3.63 Å20 Å2
3----4.43 Å2
Refinement stepCycle: LAST / Resolution: 2.7→104.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8248 0 44 137 8429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0198528
X-RAY DIFFRACTIONr_bond_other_d00.027996
X-RAY DIFFRACTIONr_angle_refined_deg1.3761.9511606
X-RAY DIFFRACTIONr_angle_other_deg3.68318368
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.78551043
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.99823.377382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.952151358
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9021554
X-RAY DIFFRACTIONr_chiral_restr0.0770.21281
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0219683
X-RAY DIFFRACTIONr_gen_planes_other0.0050.021985
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9475.5554181
X-RAY DIFFRACTIONr_mcbond_other2.9475.5554182
X-RAY DIFFRACTIONr_mcangle_it4.7388.3235219
X-RAY DIFFRACTIONr_mcangle_other4.7388.3235219
X-RAY DIFFRACTIONr_scbond_it4.1895.7614347
X-RAY DIFFRACTIONr_scbond_other4.1895.7614347
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.1978.5236387
X-RAY DIFFRACTIONr_long_range_B_refined7.96743.9489629
X-RAY DIFFRACTIONr_long_range_B_other7.96743.9489629
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 59866 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.341 190 -
Rwork0.334 3758 -
obs--99.82 %

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