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- PDB-5tcj: Crystal structure of tryptophan synthase from M. tuberculosis - a... -

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Basic information

Entry
Database: PDB / ID: 5tcj
TitleCrystal structure of tryptophan synthase from M. tuberculosis - aminoacrylate and BRD4592-bound form
Components(Tryptophan synthase ...) x 2
KeywordsLYASE / PLP / heterotetramer / amino acid biosynthesis / substrate channeling / allostery / Structural Genomics / Center for Structural Genomics of Infectious Diseases / CSGID
Function / homology
Function and homology information


tryptophan synthase / tryptophan synthase activity / tryptophan biosynthetic process / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tryptophan synthase, alpha chain / Tryptophan synthase, alpha chain, active site / Tryptophan synthase alpha chain / Tryptophan synthase alpha chain signature. / Tryptophan synthase, beta chain, conserved site / Tryptophan synthase, beta chain / Tryptophan synthase beta chain/beta chain-like / Tryptophan synthase beta chain pyridoxal-phosphate attachment site. / Rossmann fold - #1100 / Pyridoxal-phosphate dependent enzyme ...Tryptophan synthase, alpha chain / Tryptophan synthase, alpha chain, active site / Tryptophan synthase alpha chain / Tryptophan synthase alpha chain signature. / Tryptophan synthase, beta chain, conserved site / Tryptophan synthase, beta chain / Tryptophan synthase beta chain/beta chain-like / Tryptophan synthase beta chain pyridoxal-phosphate attachment site. / Rossmann fold - #1100 / Pyridoxal-phosphate dependent enzyme / Tryptophan synthase beta subunit-like PLP-dependent enzyme / Pyridoxal-phosphate dependent enzyme / Ribulose-phosphate binding barrel / Aldolase class I / Aldolase-type TIM barrel / TIM Barrel / Alpha-Beta Barrel / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-79V / : / FORMIC ACID / MALONATE ION / Chem-P1T / Tryptophan synthase beta chain / Tryptophan synthase alpha chain
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsMichalska, K. / Maltseva, N. / Jedrzejczak, R. / Wellington, S. / Nag, P.P. / Fisher, S.L. / Schreiber, S.L. / Hung, D.T. / Joachimiak, A. / Center for Structural Genomics of Infectious Diseases (CSGID)
Funding support United States, Canada, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201200026C United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272200700058C United States
Structure-guided Drug Discovery Coalition Canada
CitationJournal: Nat. Chem. Biol. / Year: 2017
Title: A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase.
Authors: Wellington, S. / Nag, P.P. / Michalska, K. / Johnston, S.E. / Jedrzejczak, R.P. / Kaushik, V.K. / Clatworthy, A.E. / Siddiqi, N. / McCarren, P. / Bajrami, B. / Maltseva, N.I. / Combs, S. / ...Authors: Wellington, S. / Nag, P.P. / Michalska, K. / Johnston, S.E. / Jedrzejczak, R.P. / Kaushik, V.K. / Clatworthy, A.E. / Siddiqi, N. / McCarren, P. / Bajrami, B. / Maltseva, N.I. / Combs, S. / Fisher, S.L. / Joachimiak, A. / Schreiber, S.L. / Hung, D.T.
History
DepositionSep 15, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 26, 2017Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 30, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Apr 13, 2022Group: Author supporting evidence / Database references / Derived calculations
Category: database_2 / pdbx_audit_support ...database_2 / pdbx_audit_support / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _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_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _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.ptnr1_symmetry / _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 / _struct_conn.ptnr2_symmetry
Revision 1.5Oct 4, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tryptophan synthase alpha chain
B: Tryptophan synthase beta chain
G: Tryptophan synthase alpha chain
H: Tryptophan synthase beta chain
E: Tryptophan synthase alpha chain
F: Tryptophan synthase beta chain
C: Tryptophan synthase alpha chain
D: Tryptophan synthase beta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)292,67551
Polymers287,6568
Non-polymers5,01943
Water12,971720
1
A: Tryptophan synthase alpha chain
B: Tryptophan synthase beta chain
C: Tryptophan synthase alpha chain
D: Tryptophan synthase beta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,31224
Polymers143,8284
Non-polymers2,48420
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
G: Tryptophan synthase alpha chain
H: Tryptophan synthase beta chain
E: Tryptophan synthase alpha chain
F: Tryptophan synthase beta chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,36327
Polymers143,8284
Non-polymers2,53523
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.092, 159.875, 165.331
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Tryptophan synthase ... , 2 types, 8 molecules AGECBHFD

#1: Protein
Tryptophan synthase alpha chain


Mass: 28579.449 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Strain: ATCC 25618 / H37Rv / Gene: trpA, Rv1613, MTCY01B2.05 / Plasmid: pMCSG81, pMCSG81-pRSF
Details (production host): pMCSG81 coexpresses TrpA and TrpB, pMCSG81-pRSF provides additional copy of TrpA
Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Gold (DE3) / References: UniProt: P9WFY1, tryptophan synthase
#2: Protein
Tryptophan synthase beta chain


Mass: 43334.598 Da / Num. of mol.: 4 / Fragment: UNP residues 13-422
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Strain: ATCC 25618 / H37Rv / Gene: trpB, Rv1612, MTCY01B2.04 / Plasmid: pMCSG81
Details (production host): pMCSG81 coexpresses TrpA and TrpB
Production host: Escherichia coli (E. coli) / Strain (production host): BL21-Gold (DE3) / References: UniProt: P9WFX9, tryptophan synthase

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Non-polymers , 6 types, 763 molecules

#3: Chemical
ChemComp-MLI / MALONATE ION / Malonic acid


Mass: 102.046 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H2O4
#4: Chemical...
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 22 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical
ChemComp-P1T / 2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC ACID


Mass: 318.220 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H15N2O7P
#6: Chemical
ChemComp-CS / CESIUM ION


Mass: 132.905 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: Cs
#7: Chemical
ChemComp-79V / (2R,3S,4R)-3-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-(hydroxymethyl)azetidine-2-carbonitrile / BRD4592


Mass: 282.312 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H15FN2O
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 720 / 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: 3.1 Å3/Da / Density % sol: 60.37 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 8% tacsimate pH 8.0, 20% PEG3350, 10 mM BaCl2, 1 mM BRD4592, soaked with 100 mM CsCl and 50 mM L-Ser, cryo 16% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97934 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Nov 16, 2015 / Details: mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 138958 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 6.3 % / Rmerge(I) obs: 0.138 / Net I/σ(I): 12.96
Reflection shellResolution: 2.4→2.44 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0 / Mean I/σ(I) obs: 1.69 / CC1/2: 0.649 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
HKL-3000data reduction
HKL-3000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TCF

5tcf


Resolution: 2.4→30 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.94 / SU B: 13.496 / SU ML: 0.155 / Cross valid method: THROUGHOUT / ESU R: 0.264 / ESU R Free: 0.197 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21074 2712 2 %RANDOM
Rwork0.18024 ---
obs0.18082 136019 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 41.368 Å2
Baniso -1Baniso -2Baniso -3
1-0.92 Å20 Å20 Å2
2--1.48 Å20 Å2
3----2.4 Å2
Refinement stepCycle: 1 / Resolution: 2.4→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms19082 0 271 720 20073
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01919824
X-RAY DIFFRACTIONr_bond_other_d0.0020.0218847
X-RAY DIFFRACTIONr_angle_refined_deg1.2911.9626906
X-RAY DIFFRACTIONr_angle_other_deg0.9332.99943090
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.79552603
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.93722.83834
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.61152954
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2915187
X-RAY DIFFRACTIONr_chiral_restr0.0670.23007
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02123090
X-RAY DIFFRACTIONr_gen_planes_other0.0010.024593
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_it0.5522.39110421
X-RAY DIFFRACTIONr_mcbond_other0.5522.39110422
X-RAY DIFFRACTIONr_mcangle_it0.9733.58113021
X-RAY DIFFRACTIONr_mcangle_other0.9733.58113014
X-RAY DIFFRACTIONr_scbond_it0.6582.5149403
X-RAY DIFFRACTIONr_scbond_other0.652.4999357
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.1183.7213878
X-RAY DIFFRACTIONr_long_range_B_refined3.10828.76721287
X-RAY DIFFRACTIONr_long_range_B_other3.10728.76721287
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.403→2.465 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.287 204 -
Rwork0.264 9628 -
obs--96.91 %
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)
13.0687-0.42210.77591.0680.07412.00690.09990.286-0.2448-0.0967-0.077-0.2530.17850.1929-0.02290.03820.00180.0330.23820.02520.258486.4266-12.947416.6739
21.0941-0.1048-0.47020.90390.36071.24480.0457-0.0123-0.0102-0.0058-0.0347-0.1143-0.05730.0879-0.01110.006-0.0116-0.00140.09330.04420.037451.3324-5.021328.7664
32.54790.2348-0.12621.328-0.52641.83720.0882-0.1132-0.15170.04010.01280.2917-0.0086-0.1521-0.1010.03020.03990.03750.1929-0.01890.206-18.045713.526414.9585
41.2237-0.1222-0.57320.9066-0.11741.21620.047-0.04130.0441-0.0096-0.01970.0893-0.0789-0.0937-0.02730.0086-0.0021-0.00150.074-0.02440.028616.36273.70352.4071
53.27341.4389-0.16972.19090.27052.1956-0.63590.6462-0.1827-1.05940.3575-0.33810.38590.15870.27840.8114-0.14580.2470.2801-0.07760.185941.5156-35.9993-47.3452
60.53380.0695-0.57751.1883-0.22052.1416-0.0770.0143-0.0853-0.11-0.0241-0.0420.2566-0.03180.1010.05-0.01120.01970.0413-0.02030.05231.5206-24.1047-12.745
71.9245-1.0790.06743.3599-0.65951.8334-0.0853-0.28630.06121.00130.03360.3523-0.3388-0.18450.05170.4118-0.07130.18070.1869-0.02460.17829.2832-26.882278.2469
80.53980.224-0.4240.94270.3041.8789-0.03-0.0035-0.04810.0172-0.03960.03470.0957-0.08570.06960.0105-0.0250.00190.08710.01490.038824.5043-21.994443.6858
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 267
2X-RAY DIFFRACTION2B9 - 407
3X-RAY DIFFRACTION3G9 - 267
4X-RAY DIFFRACTION4H7 - 407
5X-RAY DIFFRACTION5E9 - 265
6X-RAY DIFFRACTION6F9 - 407
7X-RAY DIFFRACTION7C8 - 266
8X-RAY DIFFRACTION8D9 - 407

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