9drk

Crystal structure of Mycobacterium tuberculosis biotin protein ligase in complex with Bio-1

spinqualitylabelsall models 9drk, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9drk is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.13Å Ligands: A1BGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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). 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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