7KE2

Crystal structure of Staphylococcus aureus ketol-acid reductoisomerase in complex with Mg2+ and NSC116565

Summary for 7KE2

• Entry DOI: 10.2210/pdb7ke2/pdb
• Descriptor: Ketol-acid reductoisomerase (NADP(+)), MAGNESIUM ION, 6-hydroxy-2-methyl[1,3]thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione, ... (4 entities in total)
• Functional Keywords: reductoisomerase, inhibitor, metal binding protein, isomerase, oxidoreductase
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 2
• Total formula weight: 76268.88

Authors

Kurz, J.L.,Patel, K.P.,Guddat, L.W. (deposition date: 2020-10-09, release date: 2021-07-14, Last modification date: 2023-10-18)

Primary citation

Lin, X.,Kurz, J.L.,Patel, K.M.,Wun, S.J.,Hussein, W.M.,Lonhienne, T.,West, N.P.,McGeary, R.P.,Schenk, G.,Guddat, L.W.
Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol-Acid Reductoisomerase.
Chemistry, 27:3130-3141, 2021

PubMed Abstract: New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug-resistant tuberculosis (TB). Herein, the National Cancer Institute Developmental Therapeutic Program (NCI-DTP) chemical library was screened against a promising new target, ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway. From this library, 6-hydroxy-2-methylthiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (NSC116565) was identified as a potent time-dependent inhibitor of Mycobacterium tuberculosis (Mt) KARI with a K of 95.4 nm. Isothermal titration calorimetry studies showed that this inhibitor bound to MtKARI in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH), which was confirmed by crystal structures of the compound in complex with closely related Staphylococcus aureus KARI. It is also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC values of 2.93 and 6.06 μm, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti-TB drug development.

PubMed: 33215746
DOI: 10.1002/chem.202004665

Experimental method

X-RAY DIFFRACTION (2.59 Å)