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==Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the ribose== | ==Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the ribose== | ||
<StructureSection load='4xu3' size='340' side='right' caption='[[4xu3]], [[Resolution|resolution]] 2.24Å' scene=''> | <StructureSection load='4xu3' size='340' side='right'caption='[[4xu3]], [[Resolution|resolution]] 2.24Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xu3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XU3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XU3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xu3]] is a 2 chain structure with sequence from [http://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=4XU3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XU3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=44R:N-({2-[(6-AMINO-9H-PURIN-9-YL)METHOXY]ETHYL}SULFAMOYL)-5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANAMIDE'>44R</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=44R:N-({2-[(6-AMINO-9H-PURIN-9-YL)METHOXY]ETHYL}SULFAMOYL)-5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANAMIDE'>44R</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></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]], [[4xty|4xty]], [[4xtz|4xtz]], [[4xu0|4xu0]], [[4xu1|4xu1]], [[4xu2|4xu2]]</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]], [[4xty|4xty]], [[4xtz|4xtz]], [[4xu0|4xu0]], [[4xu1|4xu1]], [[4xu2|4xu2]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">birA, CH81_03124, CH82_03406, CH84_03412, CH85_03111, CH87_01691, CH88_02592, CO60_3782, ER17_17395, FF22_02902, FI98_01129, IQ38_01820, IQ39_01720, IQ40_01775, IQ41_01700, IQ42_01770, IQ43_01710, IQ44_01750, IQ45_01765, IQ46_01705, IQ47_01735, IQ48_01770, IU12_01860, IU13_01785, IU14_01730, IU16_01770, IU17_01745, IU18_01730, IU19_01775, IU20_01750, IU22_01755, IU23_01750, IU24_01735, IZ84_17515, JE53_17495, LJ70_17695, T209_01770 ([http://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'>[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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xu3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xu3 OCA], [http://pdbe.org/4xu3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xu3 RCSB], [http://www.ebi.ac.uk/pdbsum/4xu3 PDBsum]</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=4xu3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xu3 OCA], [http://pdbe.org/4xu3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xu3 RCSB], [http://www.ebi.ac.uk/pdbsum/4xu3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xu3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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</div> | </div> | ||
<div class="pdbe-citations 4xu3" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 4xu3" 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: Large Structures]] | |||
[[Category: Finzel, B C]] | [[Category: Finzel, B C]] | ||
[[Category: Mora-Rey, T De la]] | [[Category: Mora-Rey, T De la]] | ||
Revision as of 03:10, 6 June 2019
Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the riboseMycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the ribose
Structural highlights
Publication Abstract from PubMedMycobacterium 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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