2a8x: Difference between revisions

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<StructureSection load='2a8x' size='340' side='right'caption='[[2a8x]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
<StructureSection load='2a8x' size='340' side='right'caption='[[2a8x]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2a8x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A8X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A8X FirstGlance]. <br>
<table><tr><td colspan='2'>[[2a8x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A8X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2A8X FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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]] 2.4&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Rv0462, MT0478, lpdC ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydrolipoyl_dehydrogenase Dihydrolipoyl dehydrogenase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.4 1.8.1.4] </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=2a8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a8x OCA], [https://pdbe.org/2a8x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a8x RCSB], [https://www.ebi.ac.uk/pdbsum/2a8x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a8x 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=2a8x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2a8x OCA], [https://pdbe.org/2a8x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2a8x RCSB], [https://www.ebi.ac.uk/pdbsum/2a8x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2a8x ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/DLDH_MYCTU DLDH_MYCTU]] Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>  Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>  Appears to be essential for Mtb pathogenesis.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>
[https://www.uniprot.org/uniprot/DLDH_MYCTU DLDH_MYCTU] Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>  Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>  Appears to be essential for Mtb pathogenesis.<ref>PMID:11560483</ref> <ref>PMID:11799204</ref> <ref>PMID:16045627</ref> <ref>PMID:21238944</ref> <ref>PMID:16093239</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2a8x ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2a8x ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We report the 2.4 A crystal structure for lipoamide dehydrogenase encoded by lpdC from Mycobacterium tuberculosis. Based on the Lpd structure and sequence alignment between bacterial and eukaryotic Lpd sequences, we generated single point mutations in Lpd and assayed the resulting proteins for their ability to catalyze lipoamide reduction/oxidation alone and in complex with other proteins that participate in pyruvate dehydrogenase and peroxidase activities. The results suggest that amino acid residues conserved in mycobacterial species but not conserved in eukaryotic Lpd family members modulate either or both activities and include Arg-93, His-98, Lys-103, and His-386. In addition, Arg-93 and His-386 are involved in forming both "open" and "closed" active site conformations, suggesting that these residues play a role in dynamically regulating Lpd function. Taken together, these data suggest protein surfaces that should be considered while developing strategies for inhibiting this enzyme.
Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis.,Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239<ref>PMID:16093239</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2a8x" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dihydrolipoyl dehydrogenase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bryk, R]]
[[Category: Buglino, J A]]
[[Category: Kniewel, R]]
[[Category: Lima, C D]]
[[Category: Nathan, C F]]
[[Category: Rajashankar, K R]]
[[Category: Alpha keto acid dehydrogenase]]
[[Category: Lipoamide dehydrogenase]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Oxidoreductase]]
[[Category: Bryk R]]
[[Category: Pyruvate dehydrogenase]]
[[Category: Buglino JA]]
[[Category: Kniewel R]]
[[Category: Lima CD]]
[[Category: Nathan CF]]
[[Category: Rajashankar KR]]

Revision as of 09:23, 3 April 2024

Crystal Structure of Lipoamide Dehydrogenase from Mycobacterium tuberculosisCrystal Structure of Lipoamide Dehydrogenase from Mycobacterium tuberculosis

Structural highlights

2a8x is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DLDH_MYCTU Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.[1] [2] [3] [4] [5] Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.[6] [7] [8] [9] [10] Appears to be essential for Mtb pathogenesis.[11] [12] [13] [14] [15]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
  2. ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
  3. ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
  4. ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
  5. ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200
  6. ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
  7. ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
  8. ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
  9. ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
  10. ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200
  11. ↑ Argyrou A, Blanchard JS. Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes. Biochemistry. 2001 Sep 25;40(38):11353-63. PMID:11560483
  12. ↑ Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science. 2002 Feb 8;295(5557):1073-7. Epub 2002 Jan 17. PMID:11799204 doi:10.1126/science.1067798
  13. ↑ Tian J, Bryk R, Shi S, Erdjument-Bromage H, Tempst P, Nathan C. Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes. Mol Microbiol. 2005 Aug;57(3):859-68. PMID:16045627 doi:http://dx.doi.org/MMI4741
  14. ↑ Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C. Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. Cell Host Microbe. 2011 Jan 20;9(1):21-31. doi: 10.1016/j.chom.2010.12.004. PMID:21238944 doi:http://dx.doi.org/10.1016/j.chom.2010.12.004
  15. ↑ Rajashankar KR, Bryk R, Kniewel R, Buglino JA, Nathan CF, Lima CD. Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis. J Biol Chem. 2005 Oct 7;280(40):33977-83. Epub 2005 Aug 10. PMID:16093239 doi:10.1074/jbc.M507466200

2a8x, resolution 2.40Å

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