4XEW
Crystal structure of 7,8-diaminopelargonic acid synthase (BioA) from Mycobacterium tuberculosis, complexed with a HTS lead compound
Summary for 4XEW
| Entry DOI | 10.2210/pdb4xew/pdb |
| Descriptor | Adenosylmethionine-8-amino-7-oxononanoate aminotransferase, PYRIDOXAL-5'-PHOSPHATE, 6-(2-fluorophenyl)[1,3]dioxolo[4,5-g]quinolin-8(5H)-one, ... (4 entities in total) |
| Functional Keywords | inhibitor complex transaminase plp, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 2 |
| Total formula weight | 98133.83 |
| Authors | Finzel, B.C.,Dai, R. (deposition date: 2014-12-25, release date: 2015-07-08, Last modification date: 2023-09-27) |
| Primary citation | Dai, R.,Geders, T.W.,Liu, F.,Park, S.W.,Schnappinger, D.,Aldrich, C.C.,Finzel, B.C. Fragment-Based Exploration of Binding Site Flexibility in Mycobacterium tuberculosis BioA. J.Med.Chem., 58:5208-5217, 2015 Cited by PubMed Abstract: The PLP-dependent transaminase (BioA) of Mycobacterium tuberculosis and other pathogens that catalyzes the second step of biotin biosynthesis is a now well-validated target for antibacterial development. Fragment screening by differential scanning fluorimetry has been performed to discover new chemical scaffolds and promote optimization of existing inhibitors. Calorimetry confirms binding of six molecules with high ligand efficiency. Thermodynamic data identifies which molecules bind with the enthalpy driven stabilization preferred in compounds that represent attractive starting points for future optimization. Crystallographic characterization of complexes with these molecules reveals the dynamic nature of the BioA active site. Different side chain conformational states are stabilized in response to binding by different molecules. A detailed analysis of conformational diversity in available BioA structures is presented, resulting in the identification of two states that might be targeted with molecular scaffolds incorporating well-defined conformational attributes. This new structural data can be used as part of a scaffold hopping strategy to further optimize existing inhibitors or create new small molecules with improved therapeutic potential. PubMed: 26068403DOI: 10.1021/acs.jmedchem.5b00092 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.47 Å) |
Structure validation
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