4cvy

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the M. tuberculosis sulfate ester dioxygenase Rv3406 in complex with iron.

Structural highlights

4cvy is a 4 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 2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ATSK_MYCTU Alpha-ketoglutarate-dependent sulfate ester dioxygenase, which oxidizes medium-chain alkyl-sulfate esters (PubMed:23762287). Shows preference for 2-ethylhexyl sulfate (2-EHS) in vitro, leading to the formation of succinate and 2-ethylhexanal (PubMed:23762287, PubMed:25427196). Has likely a role in sulfate scavenging in vivo (PubMed:23762287).^[1] ^[2] Also causes the inactivation of the 2-carboxyquinoxaline Ty38c (an antitubercular compound that inhibits DprE1) via oxidative decarboxylation, using Ty38c instead of alpha-ketoglutarate as a substrate. Is thus responsible for primary resistance of M.tuberculosis to Ty38c in vitro. Overexpression of Rv3406 causes resistance to Ty38c.^[3]

Publication Abstract from PubMed

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 muM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.

2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1.,Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, de Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST ACS Chem Biol. 2014 Dec 9. PMID:25427196^[4]

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

References

↑ Sogi KM, Gartner ZJ, Breidenbach MA, Appel MJ, Schelle MW, Bertozzi CR. Mycobacterium tuberculosis Rv3406 Is a Type II Alkyl Sulfatase Capable of Sulfate Scavenging. PLoS One. 2013 Jun 6;8(6):e65080. doi: 10.1371/journal.pone.0065080. Print 2013. PMID:23762287 doi:10.1371/journal.pone.0065080
↑ Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, de Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1. ACS Chem Biol. 2014 Dec 9. PMID:25427196 doi:http://dx.doi.org/10.1021/cb5007163
↑ Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, de Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1. ACS Chem Biol. 2014 Dec 9. PMID:25427196 doi:http://dx.doi.org/10.1021/cb5007163
↑ Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, de Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST. 2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1. ACS Chem Biol. 2014 Dec 9. PMID:25427196 doi:http://dx.doi.org/10.1021/cb5007163

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/4cvy"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the M. tuberculosis sulfate ester dioxygenase Rv3406 in complex with iron.==
-<StructureSection load='4cvy' size='340' side='right' caption='[[4cvy]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='4cvy' size='340' side='right'caption='[[4cvy]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4cvy]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CVY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CVY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4cvy]] is a 4 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=4CVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CVY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</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&#8491;</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=4cvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cvy OCA], [http://pdbe.org/4cvy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cvy RCSB], [http://www.ebi.ac.uk/pdbsum/4cvy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cvy ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene></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=4cvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cvy OCA], [https://pdbe.org/4cvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cvy RCSB], [https://www.ebi.ac.uk/pdbsum/4cvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cvy ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/ATSK_MYCTU ATSK_MYCTU] Alpha-ketoglutarate-dependent sulfate ester dioxygenase, which oxidizes medium-chain alkyl-sulfate esters (PubMed:23762287). Shows preference for 2-ethylhexyl sulfate (2-EHS) in vitro, leading to the formation of succinate and 2-ethylhexanal (PubMed:23762287, PubMed:25427196). Has likely a role in sulfate scavenging in vivo (PubMed:23762287).<ref>PMID:23762287</ref> <ref>PMID:25427196</ref>   Also causes the inactivation of the 2-carboxyquinoxaline Ty38c (an antitubercular compound that inhibits DprE1) via oxidative decarboxylation, using Ty38c instead of alpha-ketoglutarate as a substrate. Is thus responsible for primary resistance of M.tuberculosis to Ty38c in vitro. Overexpression of Rv3406 causes resistance to Ty38c.<ref>PMID:25427196</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Binda, C]]
+[[Category: Large Structures]]
-[[Category: Brodin, P]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Carta, A]]
+[[Category: Binda C]]
-[[Category: Chiarelli, L R]]
+[[Category: Brodin P]]
-[[Category: Cole, S T]]
+[[Category: Carta A]]
-[[Category: Costi, M P]]
+[[Category: Chiarelli LR]]
-[[Category: Delorme, V]]
+[[Category: Cole ST]]
-[[Category: Dhar, N]]
+[[Category: Costi MP]]
-[[Category: Farina, D]]
+[[Category: De Rossi E]]
-[[Category: Ferrari, S]]
+[[Category: Delorme V]]
-[[Category: Gadupudi, R]]
+[[Category: Dhar N]]
-[[Category: Hartkoorn, R C]]
+[[Category: Farina D]]
-[[Category: Kolly, G S]]
+[[Category: Ferrari S]]
-[[Category: Landry, V]]
+[[Category: Gadupudi R]]
-[[Category: Luciani, R]]
+[[Category: Hartkoorn RC]]
-[[Category: Makarov, V]]
+[[Category: Kolly GS]]
-[[Category: Molteni, E]]
+[[Category: Landry V]]
-[[Category: Mori, G]]
+[[Category: Luciani R]]
-[[Category: Neres, J]]
+[[Category: Makarov V]]
-[[Category: Pasca, M]]
+[[Category: Molteni E]]
-[[Category: Pojer, F]]
+[[Category: Mori G]]
-[[Category: Porta, A]]
+[[Category: Neres J]]
-[[Category: Ribeiro, A L.de Jesus Lopes]]
+[[Category: Pasca M]]
-[[Category: Riccardi, G]]
+[[Category: Pojer F]]
-[[Category: Rossi, E De]]
+[[Category: Porta A]]
-[[Category: Salina, S]]
+[[Category: Riccardi G]]
-[[Category: Saxena, P]]
+[[Category: Salina S]]
-[[Category: Venturelli, A]]
+[[Category: Saxena P]]
-[[Category: Zanoni, G]]
+[[Category: Venturelli A]]
-[[Category: Dioxygenase]]
+[[Category: Zanoni G]]
-[[Category: Dpre1]]
+[[Category: De Jesus Lopes Ribeiro AL]]
-[[Category: Drug design]]
-[[Category: Mycobacterial enzyme]]
-[[Category: Oxidoreductase]]

4cvy

From Proteopedia

Current revision

Crystal structure of the M. tuberculosis sulfate ester dioxygenase Rv3406 in complex with iron.

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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