View source for 9drn


==Crystal structure of Mycobacterium tuberculosis biotin protein ligase in complex with Bio-4==
<StructureSection load='9drn' size='340' side='right'caption='[[9drn]], [[Resolution|resolution]] 2.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9drn]] 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=9DRN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DRN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.98&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BGF:5-deoxy-5-(4-{5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentyl}-1H-1,2,3-triazol-1-yl)adenosine'>A1BGF</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=9drn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9drn OCA], [https://pdbe.org/9drn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9drn RCSB], [https://www.ebi.ac.uk/pdbsum/9drn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9drn ProSAT]</span></td></tr>
</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;">
== Publication Abstract from PubMed ==
The antibacterial agent Bio-AMS is metabolized in vivo through hydrolysis of the central acyl-sulfamide linker leading to high clearance and release of a moderately cytotoxic metabolite M1. Herein, we disclose analogues designed to prevent the metabolism of the central acyl-sulfamide moiety through steric hindrance or attenuation of the acyl-sulfamide electrophilicity. Bio-9 was identified as a metabolically stable analogue with a single-digit nanomolar dissociation constant for biotin protein ligase (BPL) and minimum inhibitory concentrations (MICs) against Mycobacterium tuberculosis and Staphylococcus aureus ranging from 0.2 to 20 muM. The antibacterial activity of Bio-9 was dependent on BPL expression level and was more than 70-fold better against a strain underexpressing BPL and, conversely, more than 5-fold less effective against a strain overexpressing BPL. Pharmacokinetic and metabolic studies demonstrated that Bio-9 was metabolically stable in vivo, showing negligible hydrolysis that translated to substantially reduced clearance and concomitantly boosted drug exposure and half-life compared to Bio-AMS.

Metabolically Stable Adenylation Inhibitors of Biotin Protein Ligase as Antibacterial Agents.,Liu Q, Engelhart CA, Wallach JB, Tiwari D, Ge P, Manna A, Panda S, McCue WM, Wong TY, Sharma S, Jayasinghe YP, Fuller J, Ronning DR, Bockman MR, Cheung A, Dartois V, Zimmerman MD, Schnappinger D, Aldrich CC J Med Chem. 2025 Feb 13;68(3):3065-3087. doi: 10.1021/acs.jmedchem.4c02299. Epub , 2025 Jan 17. PMID:39823202<ref>PMID:39823202</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 9drn" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis]]
[[Category: Aldrich CC]]
[[Category: Jayasinghe YP]]
[[Category: McCue WM]]
[[Category: Ronning DR]]