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- PDB-6fkg: Crystal structure of the M.tuberculosis MbcT-MbcA toxin-antitoxin... -

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Basic information

Entry
Database: PDB / ID: 6fkg
TitleCrystal structure of the M.tuberculosis MbcT-MbcA toxin-antitoxin complex.
Components
  • Rv1989c (MbcT)
  • Rv1990c (MbcA)
KeywordsTOXIN / Toxin-Antitoxin system Phosphorylase NAD+-binding
Function / homologyAntitoxin Xre/MbcA/ParS-like, toxin-binding domain / Antitoxin Xre/MbcA/ParS C-terminal toxin-binding domain / RES domain / RES domain / RES / Transferases; Glycosyltransferases; Pentosyltransferases / nucleotidyltransferase activity / Mycobacterial cidal antitoxin MbcA / NAD(+) phosphorylase MbcT
Function and homology information
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 1.8 Å
AuthorsFreire, D.M. / Cianci, M. / Pogenberg, V. / Schneider, T.R. / Wilmanns, M. / Parret, A.H.A.
CitationJournal: Mol Cell / Year: 2019
Title: An NAD Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.
Authors: Diana Mendes Freire / Claude Gutierrez / Acely Garza-Garcia / Anna D Grabowska / Ambre J Sala / Kanchiyaphat Ariyachaokun / Terezie Panikova / Katherine S H Beckham / André Colom / Vivian ...Authors: Diana Mendes Freire / Claude Gutierrez / Acely Garza-Garcia / Anna D Grabowska / Ambre J Sala / Kanchiyaphat Ariyachaokun / Terezie Panikova / Katherine S H Beckham / André Colom / Vivian Pogenberg / Michele Cianci / Anne Tuukkanen / Yves-Marie Boudehen / Antonio Peixoto / Laure Botella / Dmitri I Svergun / Dirk Schnappinger / Thomas R Schneider / Pierre Genevaux / Luiz Pedro Sorio de Carvalho / Matthias Wilmanns / Annabel H A Parret / Olivier Neyrolles /
Abstract: Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including ...Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.
History
DepositionJan 24, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 27, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2019Group: Data collection / Database references / Source and taxonomy
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / entity_src_gen / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _entity_src_gen.pdbx_host_org_strain / _entity_src_gen.pdbx_host_org_variant
Revision 1.2Apr 3, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Rv1989c (MbcT)
B: Rv1989c (MbcT)
C: Rv1990c (MbcA)
D: Rv1990c (MbcA)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0707
Polymers65,7944
Non-polymers2763
Water5,008278
1
A: Rv1989c (MbcT)
B: Rv1989c (MbcT)
C: Rv1990c (MbcA)
D: Rv1990c (MbcA)
hetero molecules

A: Rv1989c (MbcT)
B: Rv1989c (MbcT)
C: Rv1990c (MbcA)
D: Rv1990c (MbcA)
hetero molecules

A: Rv1989c (MbcT)
B: Rv1989c (MbcT)
C: Rv1990c (MbcA)
D: Rv1990c (MbcA)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,21121
Polymers197,38212
Non-polymers8299
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-y+1,x-y+1,z1
crystal symmetry operation3_565-x+y,-x+1,z1
Buried area32790 Å2
ΔGint-114 kcal/mol
Surface area62390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.311, 105.311, 108.712
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number173
Space group name H-MP63

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Components

#1: Protein Rv1989c (MbcT)


Mass: 20267.635 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Strain: H37Rv / Gene: Rv1989c, MTCY39.30
Production host: Mycobacterium smegmatis str. MC2 155 (bacteria)
Variant (production host): groEL1DeltaC / References: UniProt: P9WLP9
#2: Protein Rv1990c (MbcA)


Mass: 12629.413 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Strain: H37Rv / Gene: Rv1990c, MTCY39.29
Production host: Mycobacterium smegmatis str. MC2 155 (bacteria)
Variant (production host): groEL1DeltaC / References: UniProt: P9WLP7
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.64 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 288.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M ammonium sulphate, 0.1 M tri-sodium citrate pH 5.6 and 25 % PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 2.48, 0.9765
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 25, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
12.481
20.97651
ReflectionResolution: 1.8→9.99 Å / Num. obs: 62157 / % possible obs: 98.84 % / Redundancy: 10 % / Biso Wilson estimate: 42.4 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.0562 / Net I/σ(I): 21.6
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 7.5 % / Rmerge(I) obs: 1.364 / Mean I/σ(I) obs: 1.5 / Num. unique obs: 5639 / CC1/2: 0.497 / % possible all: 90.21

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
pointlessdata scaling
Aimlessdata scaling
SHELXCDphasing
SHELXDEphasing
RefinementMethod to determine structure: SAD / Resolution: 1.8→9.988 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.28
RfactorNum. reflection% reflection
Rfree0.2111 3025 4.87 %
Rwork0.1623 --
obs0.1646 62148 98.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.8→9.988 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4539 0 18 278 4835
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074672
X-RAY DIFFRACTIONf_angle_d0.9886363
X-RAY DIFFRACTIONf_dihedral_angle_d12.9861708
X-RAY DIFFRACTIONf_chiral_restr0.038719
X-RAY DIFFRACTIONf_plane_restr0.004840
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8001-1.82810.29511270.29282234X-RAY DIFFRACTION83
1.8281-1.85790.34591260.26762599X-RAY DIFFRACTION96
1.8579-1.88970.30041030.2512720X-RAY DIFFRACTION99
1.8897-1.92380.31951330.24062682X-RAY DIFFRACTION99
1.9238-1.96050.26861320.21932723X-RAY DIFFRACTION100
1.9605-2.00020.26961460.20862669X-RAY DIFFRACTION100
2.0002-2.04340.24871210.2042770X-RAY DIFFRACTION100
2.0434-2.09050.26011610.19692638X-RAY DIFFRACTION100
2.0905-2.14230.23011990.18692664X-RAY DIFFRACTION100
2.1423-2.19960.22671520.18122697X-RAY DIFFRACTION100
2.1996-2.26360.20761450.18212677X-RAY DIFFRACTION100
2.2636-2.33580.26031370.17592732X-RAY DIFFRACTION100
2.3358-2.41810.22961560.17742683X-RAY DIFFRACTION100
2.4181-2.51340.20061280.17922740X-RAY DIFFRACTION100
2.5134-2.62580.24491290.1862716X-RAY DIFFRACTION100
2.6258-2.76150.21051340.17252741X-RAY DIFFRACTION100
2.7615-2.93040.2253960.18372753X-RAY DIFFRACTION100
2.9304-3.15010.21231410.17942721X-RAY DIFFRACTION100
3.1501-3.45510.20371430.16822711X-RAY DIFFRACTION100
3.4551-3.92820.21581290.14452750X-RAY DIFFRACTION100
3.9282-4.85280.17111350.12362746X-RAY DIFFRACTION100
4.8528-9.9880.17311520.12372757X-RAY DIFFRACTION100
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)
16.73572.4794-2.19399.435-0.44162.015-0.32870.27560.29110.44650.2711-1.1736-0.35651.32980.27960.34840.041-0.06210.4657-0.00630.360119.191330.141255.9082
22.30840.7283-0.64481.9468-0.98132.84260.0390.2394-0.2297-0.19330.01510.07570.3628-0.1911-0.08820.3329-0.0021-0.08230.23520.00250.2946-0.544422.57161.5023
33.9045-1.5193-0.09992.3637-1.00221.1367-0.2643-0.4487-0.3650.30430.31930.09560.1496-0.144-0.05290.40580.0195-0.07080.320.03910.3283-6.429120.514870.5888
42.65550.81980.51063.7804-0.78445.26450.1511-0.2116-0.19830.3486-0.1976-0.456-0.0580.22020.07620.34180.0039-0.06930.270.04630.307310.758925.87965.4616
55.205-1.20392.32554.857-2.63895.29830.3573-0.1339-0.3-0.5052-0.04290.2103-0.03170.16320.07220.4563-0.0522-0.08790.25120.00780.29932.924519.682962.9078
62.6573-1.37581.66283.72052.65695.19440.68950.4683-0.0145-0.455-0.68480.070.962-0.03070.08820.98690.2394-0.12310.5663-0.01970.4455-0.768919.350650.9961
74.8239-1.2922-1.29493.1667-0.71262.3875-0.3197-0.4153-1.04030.07580.30590.48750.81020.0841-0.05720.4132-0.0111-0.07770.36340.08420.5047-9.096112.879269.7595
89.33676.46140.08746.24441.77991.9536-0.29670.45880.9290.2614-0.20880.7628-1.6525-0.14670.42720.55710.0271-0.11860.42780.10030.5245-32.042645.866252.0471
92.4526-0.8367-0.80962.51411.09772.3147-0.0651-0.1909-0.10650.1890.10740.24880.24260.014-0.0320.3078-0.0344-0.05440.26330.02110.2903-20.234228.597747.0332
104.64941.1588-1.69572.7109-0.46491.9736-0.04570.54410.0669-0.25990.02520.19020.0164-0.02870.0110.3148-0.0164-0.10140.34070.00520.2918-18.98825.132433.443
112.4271-0.14780.02182.92250.58991.778-0.09660.193-0.2476-0.0297-0.02980.2080.1212-0.08620.10330.2557-0.0302-0.10590.2263-0.00720.2517-19.513124.238538.9318
127.36890.2067-2.18092.83831.11574.019-0.25121.56950.5601-1.3938-0.07190.6639-0.2714-0.02760.16360.620.046-0.170.41150.01380.4158-27.72340.872736.3087
132.1617-0.18220.5343.47652.21053.5474-0.03980.0681-0.03450.0801-0.08420.2510.09330.05480.11470.2811-0.049-0.02840.29930.01950.3283-25.034832.83348.552
142.9842-0.4309-0.9122.28020.13462.6232-0.05610.271-0.53260.15390.17580.25710.6828-0.4855-0.07260.3679-0.0262-0.06130.31760.01720.3521-18.859615.854439.385
155.25340.9171.48773.8360.19336.2426-0.04340.2867-0.3377-0.2310.06190.0283-0.07270.8724-0.04980.3442-0.02230.04690.4333-0.0340.351417.063328.810444.4366
162.4273-1.0425-2.27645.0691-0.13413.39440.22480.4119-0.0241-0.47590.5295-0.8258-0.00290.0727-0.53380.4158-0.1211-0.00810.4669-0.06270.44412.121736.331435.1283
172.55411.13112.26951.85430.97732.006-0.21260.5277-0.554-0.05630.2497-0.3110.11240.23950.12260.385-0.09530.10130.4237-0.13250.486722.889538.562640.1796
183.27395.1391-2.12079.1609-1.02446.254-0.2066-0.19160.7892-0.1167-0.0348-0.1308-0.80530.0752-0.12140.3992-0.0469-0.06810.405-0.01050.459715.232543.017945.3737
193.55221.58790.15922.65410.17291.77570.0493-0.0233-0.2339-0.1393-0.1023-0.29090.09290.051-0.01970.2925-0.0217-0.00270.32710.00350.30954.350330.917540.5024
204.5290.8031-0.43362.673-0.74082.04940.04040.63840.2309-0.35130.1730.0901-0.1283-0.1112-0.12310.3453-0.0407-0.0090.35870.0350.3003-3.378938.193933.6895
214.21882.2695-0.6682.557-0.33551.30860.0501-0.1690.2631-0.2217-0.06290.1717-0.1085-0.0491-0.1020.32590.0032-0.00740.27610.0010.276-4.335836.32442.3784
226.6954-3.07650.04717.2935-2.05276.3438-0.0758-0.2535-0.39870.6155-0.05940.6561-0.8463-0.31510.10990.37420.03060.01260.4146-0.0070.4235-31.674443.139963.407
231.50352.26342.76193.67484.38445.42690.0912-0.2198-0.0270.9626-0.08070.94870.0846-0.7905-0.04530.49270.06820.05410.49170.10120.4656-26.112839.371172.4773
246.616-2.01471.92391.17140.27221.9864-0.3964-0.68280.0260.39340.46430.058-0.1426-0.2071-0.03710.38010.08160.03830.29860.0280.3634-28.044352.155870.2548
257.6533-5.1031-0.82517.98680.6230.2622-0.06740.22530.96160.14890.0681-0.92860.29360.0833-0.11330.4610.02880.03850.30460.04060.3795-25.450655.867263.5079
261.7478-2.44040.50894.0623-0.82022.2125-0.1992-0.2326-0.16580.4160.06310.0874-0.0393-0.2369-0.01570.29690.038-0.01840.31240.02880.3068-19.762337.732269.2969
274.5979-1.04830.07842.89750.91585.3531-0.2296-0.4360.63390.63860.6315-0.9086-0.14050.4381-0.43260.42240.0735-0.10310.3471-0.11170.4532-7.680240.807174.008
282.1398-2.4311-0.27664.7307-0.42981.7081-0.0274-0.03670.38110.39350.0195-0.6053-0.01240.11740.02720.3193-0.009-0.06730.27620.00010.3746-9.86838.089766.1515
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 5:12)
2X-RAY DIFFRACTION2(chain A and resid 13:53)
3X-RAY DIFFRACTION3(chain A and resid 54:101)
4X-RAY DIFFRACTION4(chain A and resid 102:149)
5X-RAY DIFFRACTION5(chain A and resid 150:157)
6X-RAY DIFFRACTION6(chain A and resid 158:162)
7X-RAY DIFFRACTION7(chain A and resid 163:186)
8X-RAY DIFFRACTION8(chain B and resid 4:12)
9X-RAY DIFFRACTION9(chain B and resid 13:58)
10X-RAY DIFFRACTION10(chain B and resid 59:75)
11X-RAY DIFFRACTION11(chain B and resid 76:109)
12X-RAY DIFFRACTION12(chain B and resid 110:124)
13X-RAY DIFFRACTION13(chain B and resid 125:161)
14X-RAY DIFFRACTION14(chain B and resid 162:186)
15X-RAY DIFFRACTION15(chain C and resid 2:14)
16X-RAY DIFFRACTION16(chain C and resid 15:29)
17X-RAY DIFFRACTION17(chain C and resid 30:46)
18X-RAY DIFFRACTION18(chain C and resid 47:51)
19X-RAY DIFFRACTION19(chain C and resid 52:70)
20X-RAY DIFFRACTION20(chain C and resid 71:88)
21X-RAY DIFFRACTION21(chain C and resid 89:113)
22X-RAY DIFFRACTION22(chain D and resid 2:14)
23X-RAY DIFFRACTION23(chain D and resid 15:20)
24X-RAY DIFFRACTION24(chain D and resid 21:43)
25X-RAY DIFFRACTION25(chain D and resid 44:51)
26X-RAY DIFFRACTION26(chain D and resid 52:74)
27X-RAY DIFFRACTION27(chain D and resid 75:87)
28X-RAY DIFFRACTION28(chain D and resid 88:113)

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