4f4q
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<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> | <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" 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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.619Å</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='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'>[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> | ||
</table> | </table> | ||
== Function == | == 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> | [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 == | ||
| - | 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. | ||
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| - | 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<ref>PMID:22956199</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4f4q" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 15:16, 14 March 2024
Crystal structure of M. smegmatis DprE1 in complex with FAD and covalently bound BTZ043
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