4W1W
Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with 7-(diethylamino)-3-(thiophene-2-carbonyl)-2H-chromen-2-one
Summary for 4W1W
| Entry DOI | 10.2210/pdb4w1w/pdb |
| Related | 4W1W 4W1X |
| Descriptor | Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, 7-(diethylamino)-3-(thiophen-2-ylcarbonyl)-2H-chromen-2-one, ... (6 entities in total) |
| Functional Keywords | inhibitor complex transaminase plp, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium tuberculosis |
| Cellular location | Cytoplasm : P9WQ80 |
| Total number of polymer chains | 2 |
| Total formula weight | 93097.90 |
| Authors | Finzel, B.C.,Ran, D. (deposition date: 2014-08-13, release date: 2015-02-04, Last modification date: 2023-12-27) |
| Primary citation | Park, S.W.,Casalena, D.E.,Wilson, D.J.,Dai, R.,Nag, P.P.,Liu, F.,Boyce, J.P.,Bittker, J.A.,Schreiber, S.L.,Finzel, B.C.,Schnappinger, D.,Aldrich, C.C. Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis. Chem.Biol., 22:76-86, 2015 Cited by PubMed Abstract: Biotin biosynthesis is essential for survival and persistence of Mycobacterium tuberculosis (Mtb) in vivo. The aminotransferase BioA, which catalyzes the antepenultimate step in the biotin pathway, has been established as a promising target due to its vulnerability to chemical inhibition. We performed high-throughput screening (HTS) employing a fluorescence displacement assay and identified a diverse set of potent inhibitors including many diversity-oriented synthesis (DOS) scaffolds. To efficiently select only hits targeting biotin biosynthesis, we then deployed a whole-cell counterscreen in biotin-free and biotin-containing medium against wild-type Mtb and in parallel with isogenic bioA Mtb strains that possess differential levels of BioA expression. This counterscreen proved crucial to filter out compounds whose whole-cell activity was off target as well as identify hits with weak, but measurable whole-cell activity in BioA-depleted strains. Several of the most promising hits were cocrystallized with BioA to provide a framework for future structure-based drug design efforts. PubMed: 25556942DOI: 10.1016/j.chembiol.2014.11.012 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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