4XU3

Mycobacterium tuberculosis biotin ligase complexed with bisubstrate inhibitor 90 that has an acyclic ether in place of the ribose

Summary for 4XU3

• Entry DOI: 10.2210/pdb4xu3/pdb
• Related: 4XTU 4XTV 4XTW 4XTX 4XTY 4XTZ 4XU0 4XU1 4XU2
• Descriptor: Bifunctional ligase/repressor BirA, 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, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: biotin-protein ligase, bisubstrate inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 58131.50

Authors

De la Mora-Rey, T.,Finzel, B.C. (deposition date: 2015-01-24, release date: 2015-09-02, Last modification date: 2023-09-27)

Primary citation

Bockman, M.R.,Kalinda, A.S.,Petrelli, R.,De la Mora-Rey, T.,Tiwari, D.,Liu, F.,Dawadi, S.,Nandakumar, M.,Rhee, K.Y.,Schnappinger, D.,Finzel, B.C.,Aldrich, C.C.
Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.
J.Med.Chem., 58:7349-7369, 2015

PubMed Abstract: 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 K(D)s ≤ 2 nM. Additionally, we obtained high-resolution cocrystal 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 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analogue over the corresponding C-2'-β analogue, consistent with their differential whole-cell activity.

PubMed: 26299766
DOI: 10.1021/acs.jmedchem.5b00719

Experimental method

X-RAY DIFFRACTION (2.24267703977 Å)