5KGS
Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with an inhibitor optimized from HTS lead: 5-[4-(1,3-benzodioxol-5-ylcarbonyl)piperazin-1-yl]-2,3-dihydroinden-1-one
Summary for 5KGS
| Entry DOI | 10.2210/pdb5kgs/pdb |
| Related | 4W1X 4WY4 4XJO 4XJP 5KGT |
| Descriptor | Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, 5-[4-(1,3-benzodioxol-5-ylcarbonyl)piperazin-1-yl]-2,3-dihydroinden-1-one, ... (5 entities in total) |
| Functional Keywords | transaminase, plp, transferase, transferase-inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium bovis (strain ATCC BAA-935 / AF2122/97) |
| Total number of polymer chains | 2 |
| Total formula weight | 98596.46 |
| Authors | Maize, K.M.,Aldrich, C.C.,Finzel, B.C. (deposition date: 2016-06-13, release date: 2017-06-14, Last modification date: 2023-09-27) |
| Primary citation | Liu, F.,Dawadi, S.,Maize, K.M.,Dai, R.,Park, S.W.,Schnappinger, D.,Finzel, B.C.,Aldrich, C.C. Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis. J. Med. Chem., 60:5507-5520, 2017 Cited by PubMed Abstract: The pyridoxal 5'-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a K of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium. PubMed: 28594172DOI: 10.1021/acs.jmedchem.7b00189 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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