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- PDB-4zt6: Trypanosoma brucei methionyl-tRNA synthetase in complex with inhi... -

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Basic information

Entry
Database: PDB / ID: 4zt6
TitleTrypanosoma brucei methionyl-tRNA synthetase in complex with inhibitor N-[(4R)-6,8-dichloro-3,4-dihydro-2H-chromen-4-yl]-N'-(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine (Chem 1709)
ComponentsMethionyl-tRNA synthetase
KeywordsLigase/Ligase Inhibitor / ligase / aminoacyl-tRNA synthetase / aaRS / MetRS / Trypanosoma brucei / protein-inhibitor complex / Ligase-Ligase Inhibitor complex
Function / homology
Function and homology information


methionine-tRNA ligase / methionine-tRNA ligase activity / methionyl-tRNA aminoacylation / ciliary plasm / 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-4RD / METHIONINE / methionine--tRNA ligase
Similarity search - Component
Biological speciesTrypanosoma brucei brucei (eukaryote)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.25 Å
AuthorsKoh, C.-Y. / Hol, W.G.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Acs Infect Dis. / Year: 2016
Title: 5-Fluoroimidazo[4,5-b]pyridine Is a Privileged Fragment That Conveys Bioavailability to Potent Trypanosomal Methionyl-tRNA Synthetase Inhibitors.
Authors: Zhang, Z. / Koh, C.Y. / Ranade, R.M. / Shibata, S. / Gillespie, J.R. / Hulverson, M.A. / Huang, W. / Nguyen, J. / Pendem, N. / Gelb, M.H. / Verlinde, C.L. / Hol, W.G. / Buckner, F.S. / Fan, E.
History
DepositionMay 14, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 4, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2016Group: Database references
Revision 1.2Jan 15, 2020Group: Author supporting evidence / Derived calculations / Category: pdbx_audit_support / pdbx_struct_oper_list
Item: _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.3Sep 27, 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 / 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)123,7418
Polymers122,8692
Non-polymers8726
Water11,097616
1
A: Methionyl-tRNA synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8185
Polymers61,4351
Non-polymers3844
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Methionyl-tRNA synthetase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,9233
Polymers61,4351
Non-polymers4882
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.077, 106.229, 206.561
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: THR / End label comp-ID: THR / Refine code: _ / Auth seq-ID: 238 - 767 / Label seq-ID: 7 - 536

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

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Components

#1: Protein Methionyl-tRNA synthetase


Mass: 61434.707 Da / Num. of mol.: 2 / Fragment: UNP residues 237-773 / Mutation: K456A, K457R, E458A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Trypanosoma brucei brucei (eukaryote) / Strain: 927/4 GUTat10.1 / Gene: Tb10.70.6470 / Plasmid: AVA0421 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / 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-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-4RD / N-[(4R)-6,8-dichloro-3,4-dihydro-2H-chromen-4-yl]-N'-(5-fluoro-1H-imidazo[4,5-b]pyridin-2-yl)propane-1,3-diamine


Mass: 410.273 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18Cl2FN5O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 616 / 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: 3.89 Å3/Da / Density % sol: 68.36 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop
Details: 2.0-2.3 M ammonium sulfate, 0.2 M sodium chloride, 0.1 M sodium cacodylate
PH range: 6.0 to 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.954 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 25, 2014
RadiationMonochromator: Liquid nitrogen-cooled double crystal, Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.954 Å / Relative weight: 1
ReflectionResolution: 2.25→37.87 Å / Num. obs: 91234 / % possible obs: 99.7 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.116 / Net I/σ(I): 12.6
Reflection shellResolution: 2.25→2.29 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.011 / Mean I/σ(I) obs: 1.9 / % possible all: 99.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation8.65 Å37.87 Å
Translation8.65 Å37.87 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
Aimless0.3.11data scaling
PHASER2.5.6phasing
PDB_EXTRACT3.15data extraction
XDSdata reduction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EG8

4eg8


Resolution: 2.25→37.87 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.925 / SU B: 11.557 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.201 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23348 4584 5 %RANDOM
Rwork0.20768 ---
obs0.20898 86564 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.793 Å2
Baniso -1Baniso -2Baniso -3
1-4.26 Å20 Å20 Å2
2---1.28 Å2-0 Å2
3----2.99 Å2
Refinement stepCycle: LAST / Resolution: 2.25→37.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8329 0 52 616 8997
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0198596
X-RAY DIFFRACTIONr_bond_other_d0.0030.028085
X-RAY DIFFRACTIONr_angle_refined_deg1.1191.95411693
X-RAY DIFFRACTIONr_angle_other_deg0.897318563
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.28151049
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.8623.438384
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.504151366
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8541554
X-RAY DIFFRACTIONr_chiral_restr0.0660.21300
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0219709
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021985
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_it1.0592.6124214
X-RAY DIFFRACTIONr_mcbond_other1.0582.6124213
X-RAY DIFFRACTIONr_mcangle_it1.7983.9095257
X-RAY DIFFRACTIONr_mcangle_other1.7983.915258
X-RAY DIFFRACTIONr_scbond_it1.1842.7234382
X-RAY DIFFRACTIONr_scbond_other1.1842.7244383
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.9844.0266437
X-RAY DIFFRACTIONr_long_range_B_refined4.9121.52910289
X-RAY DIFFRACTIONr_long_range_B_other4.77921.20510130
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 30637 / 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: 2.25→2.308 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 355 -
Rwork0.304 6264 -
obs--99.62 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.2554-0.5603-0.53971.85550.88871.96150.08130.2029-0.1237-0.1678-0.16470.11420.0384-0.22240.08340.04050.01310.02010.1622-0.03770.0957-11.34-6.884-56.411
21.1619-0.6303-0.4511.68030.5491.3352-0.04650.024-0.0538-0.0003-0.00160.03840.0852-0.03490.04810.0278-0.00590.04850.1419-0.02170.12822.195-16.802-51.31
30.7977-0.41410.27971.08431.99956.02470.19430.2209-0.42580.3655-0.22660.25381.3819-0.28780.03230.3443-0.0321-0.03360.1885-0.2550.4959-25.636-11.938-44.467
41.1463-0.4733-0.30931.25030.24321.5737-0.03320.0333-0.10130.0675-0.01910.2376-0.1569-0.29280.05230.03090.02640.03710.1507-0.01640.1291-27.02911.498-32.085
52.51992.54120.38939.18920.512.0786-0.09220.2250.0933-0.61540.16191.21420.0224-0.6023-0.06970.18140.0211-0.01960.30410.02840.2463-32.54813.653-39.406
61.1712-0.2834-0.66130.67850.33941.6168-0.1057-0.1522-0.07440.08010.03710.08770.14470.01230.06860.01860.01460.0130.14760.00320.1071-30.70612.34210.964
71.53343.6276-0.43410.3452-0.05984.01440.0186-0.0629-0.1912-0.0117-0.2410.19690.5557-0.9190.22240.1358-0.1468-0.13730.28980.03420.5152-60.05521.15311.138
81.0738-0.4231-0.65911.01050.27991.50670.02470.0366-0.01570.0808-0.0362-0.016-0.0793-0.10010.01140.02050.01930.02440.16230.00630.1572-37.28522.6374.766
91.2574-0.2524-0.59321.14390.28121.4526-0.091-0.0207-0.16640.13510.00890.12490.30030.04040.08210.07260.01090.03510.1141-0.00930.1066-16.186-4.135-10.315
105.73612.1099-1.13293.9229-0.48532.0737-0.0615-0.6016-0.95880.30750.0236-0.29610.49940.24210.03790.18040.0949-0.030.15390.07970.1834-6.879-8.589-6.287
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A238 - 337
2X-RAY DIFFRACTION2A338 - 546
3X-RAY DIFFRACTION3A547 - 593
4X-RAY DIFFRACTION4A594 - 741
5X-RAY DIFFRACTION5A742 - 767
6X-RAY DIFFRACTION6B-4 - 351
7X-RAY DIFFRACTION7B352 - 404
8X-RAY DIFFRACTION8B405 - 546
9X-RAY DIFFRACTION9B547 - 741
10X-RAY DIFFRACTION10B742 - 767

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