6fkg

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the M.tuberculosis MbcT-MbcA toxin-antitoxin complex.

Structural highlights

6fkg is a 4 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MBCT_MYCTU Toxic component of a type II toxin-antitoxin (TA) system. Neutralized by cognate antitoxin MbcA (PubMed:30315706, PubMed:30792174). Degrades NAD(+) by phosphorolysis. Expression in the absence of its cognate antitoxin MbcA causes dramatic reduction of intracellular NAD(+) levels and is deleterious to cell growth, causing cell death. In a SCID mouse infection model, mice infected with bacteria overexpressing this protein survive longer. Overexpression of this protein in a mouse infection model at 21 days leads to bacterial death, and shows a synergistic 100-fold increase in mouse survival when combined with isoniazid treatment (PubMed:30792174).^[1] ^[2]

Publication Abstract from PubMed

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 A-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.

An NAD(+) Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death.,Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen YM, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPS, Wilmanns M, Parret AHA, Neyrolles O Mol Cell. 2019 Feb 18. pii: S1097-2765(19)30048-6. doi:, 10.1016/j.molcel.2019.01.028. PMID:30792174^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Skjerning RB, Senissar M, Winther K, Gerdes K, Brodersen DE. The RES domain toxins of RES-Xre toxin-antitoxin modules induce cell stasis by degrading NAD(). Mol Microbiol. 2018 Oct 13. doi: 10.1111/mmi.14150. PMID:30315706 doi:http://dx.doi.org/10.1111/mmi.14150
↑ Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen YM, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPS, Wilmanns M, Parret AHA, Neyrolles O. An NAD(+) Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. Mol Cell. 2019 Feb 18. pii: S1097-2765(19)30048-6. doi:, 10.1016/j.molcel.2019.01.028. PMID:30792174 doi:http://dx.doi.org/10.1016/j.molcel.2019.01.028
↑ Freire DM, Gutierrez C, Garza-Garcia A, Grabowska AD, Sala AJ, Ariyachaokun K, Panikova T, Beckham KSH, Colom A, Pogenberg V, Cianci M, Tuukkanen A, Boudehen YM, Peixoto A, Botella L, Svergun DI, Schnappinger D, Schneider TR, Genevaux P, de Carvalho LPS, Wilmanns M, Parret AHA, Neyrolles O. An NAD(+) Phosphorylase Toxin Triggers Mycobacterium tuberculosis Cell Death. Mol Cell. 2019 Feb 18. pii: S1097-2765(19)30048-6. doi:, 10.1016/j.molcel.2019.01.028. PMID:30792174 doi:http://dx.doi.org/10.1016/j.molcel.2019.01.028

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6fkg"

@@ Line 3: / Line 3: @@
 <StructureSection load='6fkg' size='340' side='right'caption='[[6fkg]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6fkg]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FKG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FKG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6fkg]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FKG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FKG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv1989c, MTCY39.30 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU]), Rv1990c, MTCY39.29 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fkg OCA], [http://pdbe.org/6fkg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fkg RCSB], [http://www.ebi.ac.uk/pdbsum/6fkg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fkg ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6fkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fkg OCA], [https://pdbe.org/6fkg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fkg RCSB], [https://www.ebi.ac.uk/pdbsum/6fkg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fkg ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/MBCT_MYCTU MBCT_MYCTU] Toxic component of a type II toxin-antitoxin (TA) system. Neutralized by cognate antitoxin MbcA (PubMed:30315706, PubMed:30792174). Degrades NAD(+) by phosphorolysis. Expression in the absence of its cognate antitoxin MbcA causes dramatic reduction of intracellular NAD(+) levels and is deleterious to cell growth, causing cell death. In a SCID mouse infection model, mice infected with bacteria overexpressing this protein survive longer. Overexpression of this protein in a mouse infection model at 21 days leads to bacterial death, and shows a synergistic 100-fold increase in mouse survival when combined with isoniazid treatment (PubMed:30792174).<ref>PMID:30315706</ref> <ref>PMID:30792174</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myctu]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Cianci, M]]
+[[Category: Cianci M]]
-[[Category: Freire, D M]]
+[[Category: Freire DM]]
-[[Category: Parret, A H.A]]
+[[Category: Parret AHA]]
-[[Category: Pogenberg, V]]
+[[Category: Pogenberg V]]
-[[Category: Schneider, T R]]
+[[Category: Schneider TR]]
-[[Category: Wilmanns, M]]
+[[Category: Wilmanns M]]
-[[Category: Toxin]]
-[[Category: Toxin-antitoxin system phosphorylase nad+-binding]]

6fkg

From Proteopedia

Current revision

Crystal structure of the M.tuberculosis MbcT-MbcA toxin-antitoxin complex.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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