7U9K
Staphylococcus aureus D-alanine-D-alanine ligase in complex with ATP, D-ala-D-ala, Mg2+ and K+
Summary for 7U9K
| Entry DOI | 10.2210/pdb7u9k/pdb |
| Descriptor | D-alanine--D-alanine ligase, DAL-DAL, POTASSIUM ION, ... (7 entities in total) |
| Functional Keywords | atp-grasp, nucleotide binding, metal binding, ligase |
| Biological source | Staphylococcus aureus subsp. aureus NCTC 8325 More |
| Total number of polymer chains | 3 |
| Total formula weight | 83996.73 |
| Authors | Pederick, J.L.,Bruning, J.B. (deposition date: 2022-03-10, release date: 2023-03-15, Last modification date: 2024-11-13) |
| Primary citation | Becker, R.,Pederick, J.L.,Dawes, E.G.,Bruning, J.B.,Abell, A.D. Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors. Bioorg.Med.Chem., 96:117509-117509, 2023 Cited by PubMed Abstract: d-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further inhibitor design. Evaluation of 8 in SaDdl enzyme inhibition assays revealed the ability to reduce enzyme activity to 72 ± 8 % (IC = 1.6 mM). The sulfamide linker of 8 was extended with 2-(4-methoxyphenyl)ethanol to give 29, to investigate further interactions with the d-Ala pocket of SaDdl, as predicted by molecular docking. This compound reduced enzyme activity to 89 ± 1 %, with replacement of the 4-methoxyphenyl group in 29 with alternative phenyl substituents (27, 28, 31-33, 35, 36) failing to significantly improve on this (80-89 % remaining enzyme activity). Exchanging these phenyl substituents with selected heterocycles (42, 46, 47) did improve activity, with the most active compound (42) reducing SaDdl activity to 70 ± 1 % (IC = 1.7 mM), which compares favourably to the FDA-approved inhibitor d-cycloserine (DCS) (IC = 0.1 mM). To the best of our knowledge, this is the first reported study of bisubstrate SaDdl inhibitors. PubMed: 37948922DOI: 10.1016/j.bmc.2023.117509 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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