4xu1: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xu1]] 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=4XU1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XU1 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xu1]] 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=4XU1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XU1 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44O:[(2S,6R)-6-(6-AMINO-9H-PURIN-9-YL)MORPHOLIN-2-YL]METHYL+{5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMATE'>44O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.7000133Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=44O:[(2S,6R)-6-(6-AMINO-9H-PURIN-9-YL)MORPHOLIN-2-YL]METHYL+{5-[(3AS,4S,6AR)-2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL]PENTANOYL}SULFAMATE'>44O</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=4xu1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xu1 OCA], [https://pdbe.org/4xu1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xu1 RCSB], [https://www.ebi.ac.uk/pdbsum/4xu1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xu1 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=4xu1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xu1 OCA], [https://pdbe.org/4xu1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xu1 RCSB], [https://www.ebi.ac.uk/pdbsum/4xu1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xu1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
Latest revision as of 10:49, 27 September 2023
Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 82 that incorporates a morpholine in place of the riboseMycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 82 that incorporates a morpholine in place of the ribose
Structural highlights
FunctionBIRA_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 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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