6VO2
Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex with Mg, NADPH and inhibitor.
Summary for 6VO2
| Entry DOI | 10.2210/pdb6vo2/pdb |
| Descriptor | Ketol-acid reductoisomerase (NADP(+)), MAGNESIUM ION, 3-(methylsulfonyl)-2-oxopropanoic acid, ... (5 entities in total) |
| Functional Keywords | reductoisomerase, inhibitor, complex, metal binding protein |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 2 |
| Total formula weight | 76035.91 |
| Authors | Bayaraa, T.,Patel, K.M.,Guddat, L.W. (deposition date: 2020-01-29, release date: 2020-04-08, Last modification date: 2023-10-11) |
| Primary citation | Bayaraa, T.,Kurz, J.L.,Patel, K.M.,Hussein, W.M.,Bilyj, J.K.,West, N.P.,Schenk, G.,McGeary, R.P.,Guddat, L.W. Discovery, Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor. Chemistry, 26:8958-8968, 2020 Cited by PubMed Abstract: Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis (Mt) KARI and identified two compounds that have K values below 200 nm. In Mt cell susceptibility assays one of these compounds exhibited an IC value of 0.8 μm. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56 % identity with Mt KARI, NADPH and Mg yielded a structure to 1.72 Å resolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data. PubMed: 32198779DOI: 10.1002/chem.202000899 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.59 Å) |
Structure validation
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