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| | ==Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 63 with Fluorine in place of 2'OH== | | ==Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 63 with Fluorine in place of 2'OH== |
| - | <StructureSection load='4xty' size='340' side='right' caption='[[4xty]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='4xty' size='340' side='right'caption='[[4xty]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4xty]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XTY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XTY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4xty]] 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=4XTY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XTY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=44L:2,5-DIDEOXY-2-FLUORO-5-[({5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMOYL)AMINO]ADENOSINE'>44L</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]] 1.8000267Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4xtu|4xtu]], [[4xtv|4xtv]], [[4xtw|4xtw]], [[4xtx|4xtx]], [[4xtz|4xtz]], [[4xu0|4xu0]], [[4xu1|4xu1]], [[4xu2|4xu2]], [[4xu3|4xu3]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44L:2,5-DIDEOXY-2-FLUORO-5-[({5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMOYL)AMINO]ADENOSINE'>44L</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Biotin--[acetyl-CoA-carboxylase]_ligase Biotin--[acetyl-CoA-carboxylase] ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.15 6.3.4.15] </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=4xty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xty OCA], [https://pdbe.org/4xty PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xty RCSB], [https://www.ebi.ac.uk/pdbsum/4xty PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xty 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=4xty FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xty OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xty RCSB], [http://www.ebi.ac.uk/pdbsum/4xty PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BIRA_MYCTU BIRA_MYCTU] Catalyzes the transfer of biotin onto a conserved lysine residue of the biotin carboxyl carrier protein (BCCP) domain of acetyl-CoA carboxylase and converts it to active holo-BCCP (PubMed:18509457, PubMed:24723382). Forms an acyl-adenylate intermediate (PubMed:18509457, PubMed:24723382). Cannot use GTP or desthiobiotin (PubMed:18509457).<ref>PMID:18509457</ref> <ref>PMID:24723382</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4xty" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Biotin Protein Ligase 3D structures|Biotin Protein Ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Finzel, B C]] | + | [[Category: Large Structures]] |
| - | [[Category: Mora-Rey, T De la]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Biotin-protein ligase]] | + | [[Category: De la Mora-Rey T]] |
| - | [[Category: Bisubstrate inhibitor]] | + | [[Category: Finzel BC]] |
| - | [[Category: Ligase-ligase inhibitor complex]]
| + | |
| Structural highlights
Function
BIRA_MYCTU Catalyzes the transfer of biotin onto a conserved lysine residue of the biotin carboxyl carrier protein (BCCP) domain of acetyl-CoA carboxylase and converts it to active holo-BCCP (PubMed:18509457, PubMed:24723382). Forms an acyl-adenylate intermediate (PubMed:18509457, PubMed:24723382). Cannot use GTP or desthiobiotin (PubMed:18509457).[1] [2]
Publication Abstract from PubMed
Mycobacterium tuberculosis (Mtb) responsible for both latent and symptomatic tuberculosis (TB) remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KD's below 2 nM. Additionally, we obtained high-resolution co-crystal structures for a majority of the compounds. Despite fairly uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MIC) ranging from 0.78 to >100 microM. Cellular accumulation studies in Mtb showed a nearly 10-fold enhanced accumulation of a C-2'-alpha analog over the corresponding C-2'-beta analog, consistent with their differential whole-cell activity.
Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.,Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC J Med Chem. 2015 Aug 24. PMID:26299766[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Purushothaman S, Gupta G, Srivastava R, Ramu VG, Surolia A. Ligand specificity of group I biotin protein ligase of Mycobacterium tuberculosis. PLoS One. 2008 May 28;3(5):e2320. doi: 10.1371/journal.pone.0002320. PMID:18509457 doi:http://dx.doi.org/10.1371/journal.pone.0002320
- ↑ Ma Q, Akhter Y, Wilmanns M, Ehebauer MT. Active site conformational changes upon reaction intermediate biotinyl-5'-AMP binding in biotin protein ligase from Mycobacterium tuberculosis. Protein Sci. 2014 Apr 9. doi: 10.1002/pro.2475. PMID:24723382 doi:http://dx.doi.org/10.1002/pro.2475
- ↑ Bockman MR, Kalinda AS, Petrelli R, De la Mora-Rey T, Tiwari D, Liu F, Dawadi S, Nandakumar M, Rhee KY, Schnappinger D, Finzel BC, Aldrich CC. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J Med Chem. 2015 Aug 24. PMID:26299766 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00719
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