4f4q

From Proteopedia

(Difference between revisions)

Revision as of 04:34, 7 October 2022

Crystal structure of M. smegmatis DprE1 in complex with FAD and covalently bound BTZ043

Structural highlights

4f4q is a 1 chain structure with sequence from Mycolicibacterium smegmatis MC2 155. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DPRE1_MYCS2 Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:22188377). DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22188377). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (By similarity). Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro (PubMed:22188377, PubMed:22956199). Appears to be essential for the growth of M.smegmatis (PubMed:21346818).[UniProtKB:P9WJF1]^[1] ^[2] ^[3]

Publication Abstract from PubMed

The benzothiazinone BTZ043 is a tuberculosis drug candidate with nanomolar whole-cell activity. BTZ043 targets the DprE1 catalytic component of the essential enzyme decaprenylphosphoryl-beta-d-ribofuranose-2'-epimerase, thus blocking biosynthesis of arabinans, vital components of mycobacterial cell walls. Crystal structures of DprE1, in its native form and in a complex with BTZ043, reveal formation of a semimercaptal adduct between the drug and an active-site cysteine, as well as contacts to a neighboring catalytic lysine residue. Kinetic studies confirm that BTZ043 is a mechanism-based, covalent inhibitor. This explains the exquisite potency of BTZ043, which, when fluorescently labeled, localizes DprE1 at the poles of growing bacteria. Menaquinone can reoxidize the flavin adenine dinucleotide cofactor in DprE1 and may be the natural electron acceptor for this reaction in the mycobacterium. Our structural and kinetic analysis provides both insight into a critical epimerization reaction and a platform for structure-based design of improved inhibitors.

Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis.,Neres J, Pojer F, Molteni E, Chiarelli LR, Dhar N, Boy-Rottger S, Buroni S, Fullam E, Degiacomi G, Lucarelli AP, Read RJ, Zanoni G, Edmondson DE, De Rossi E, Pasca MR, McKinney JD, Dyson PJ, Riccardi G, Mattevi A, Cole ST, Binda C Sci Transl Med. 2012 Sep 5;4(150):150ra121. PMID:22956199^[4]

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

References

↑ Crellin PK, Brammananth R, Coppel RL. Decaprenylphosphoryl-beta-D-ribose 2'-epimerase, the target of benzothiazinones and dinitrobenzamides, is an essential enzyme in Mycobacterium smegmatis. PLoS One. 2011 Feb 8;6(2):e16869. doi: 10.1371/journal.pone.0016869. PMID:21346818 doi:http://dx.doi.org/10.1371/journal.pone.0016869
↑ Trefzer C, Skovierova H, Buroni S, Bobovska A, Nenci S, Molteni E, Pojer F, Pasca MR, Makarov V, Cole ST, Riccardi G, Mikusova K, Johnsson K. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-beta-D-ribofuranose 2'-oxidase DprE1. J Am Chem Soc. 2012 Jan 18;134(2):912-5. doi: 10.1021/ja211042r. Epub 2011 Dec, 21. PMID:22188377 doi:http://dx.doi.org/10.1021/ja211042r
↑ Neres J, Pojer F, Molteni E, Chiarelli LR, Dhar N, Boy-Rottger S, Buroni S, Fullam E, Degiacomi G, Lucarelli AP, Read RJ, Zanoni G, Edmondson DE, De Rossi E, Pasca MR, McKinney JD, Dyson PJ, Riccardi G, Mattevi A, Cole ST, Binda C. Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis. Sci Transl Med. 2012 Sep 5;4(150):150ra121. PMID:22956199 doi:http://dx.doi.org/10.1126/scitranslmed.3004395
↑ Neres J, Pojer F, Molteni E, Chiarelli LR, Dhar N, Boy-Rottger S, Buroni S, Fullam E, Degiacomi G, Lucarelli AP, Read RJ, Zanoni G, Edmondson DE, De Rossi E, Pasca MR, McKinney JD, Dyson PJ, Riccardi G, Mattevi A, Cole ST, Binda C. Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis. Sci Transl Med. 2012 Sep 5;4(150):150ra121. PMID:22956199 doi:http://dx.doi.org/10.1126/scitranslmed.3004395

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/4f4q"

@@ Line 1: / Line 1: @@
 ==Crystal structure of M. smegmatis DprE1 in complex with FAD and covalently bound BTZ043==
-<StructureSection load='4f4q' size='340' side='right' caption='[[4f4q]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
+<StructureSection load='4f4q' size='340' side='right'caption='[[4f4q]], [[Resolution|resolution]] 2.62&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4f4q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycs2 Mycs2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F4Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F4Q FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4f4q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F4Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F4Q FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0SK:8-(HYDROXYAMINO)-2-[(2S)-2-METHYL-1,4-DIOXA-8-AZASPIRO[4.5]DEC-8-YL]-6-(TRIFLUOROMETHYL)-4H-1,3-BENZOTHIAZIN-4-ONE'>0SK</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0SK:8-(HYDROXYAMINO)-2-[(2S)-2-METHYL-1,4-DIOXA-8-AZASPIRO[4.5]DEC-8-YL]-6-(TRIFLUOROMETHYL)-4H-1,3-BENZOTHIAZIN-4-ONE'>0SK</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MSMEG_6382 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=246196 MYCS2])</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=4f4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f4q OCA], [https://pdbe.org/4f4q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f4q RCSB], [https://www.ebi.ac.uk/pdbsum/4f4q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f4q ProSAT]</span></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=4f4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f4q OCA], [http://pdbe.org/4f4q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f4q RCSB], [http://www.ebi.ac.uk/pdbsum/4f4q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f4q ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/DPRE1_MYCS2 DPRE1_MYCS2] Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:22188377). DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22188377). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (By similarity). Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro (PubMed:22188377, PubMed:22956199). Appears to be essential for the growth of M.smegmatis (PubMed:21346818).[UniProtKB:P9WJF1]<ref>PMID:21346818</ref> <ref>PMID:22188377</ref> <ref>PMID:22956199</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Mycs2]]
+[[Category: Large Structures]]
-[[Category: Binda, C]]
+[[Category: Mycolicibacterium smegmatis MC2 155]]
-[[Category: Chiarelli, L]]
+[[Category: Binda C]]
-[[Category: Cole, S T]]
+[[Category: Chiarelli L]]
-[[Category: Mattevi, A]]
+[[Category: Cole ST]]
-[[Category: Molteni, E]]
+[[Category: Mattevi A]]
-[[Category: Neres, J]]
+[[Category: Molteni E]]
-[[Category: Pojer, F]]
+[[Category: Neres J]]
-[[Category: Riccardi, G]]
+[[Category: Pojer F]]
-[[Category: Btz043 covalently bound to cys394]]
+[[Category: Riccardi G]]
-[[Category: Fad domain]]
-[[Category: Oxidase]]
-[[Category: Oxidoreductase]]

4f4q

From Proteopedia

Revision as of 04:34, 7 October 2022

Crystal structure of M. smegmatis DprE1 in complex with FAD and covalently bound BTZ043

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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