6NDL
Crystal structure of Staphylococcus aureus biotin protein ligase in complex with a sulfonamide inhibitor
Summary for 6NDL
| Entry DOI | 10.2210/pdb6ndl/pdb |
| Descriptor | Biotin Protein Ligase, GLYCEROL, 1-[4-(6-aminopurin-9-yl)butylsulfamoyl]-3-[4-[(4~{S})-2-oxidanylidene-1,3,3~{a},4,6,6~{a}-hexahydrothieno[3,4-d]imidazol-4-yl]butyl]urea, ... (4 entities in total) |
| Functional Keywords | bpl inhibitor, sulfonamide analogue, amino sulfonylurea, antibiotic, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 39058.99 |
| Authors | Marshall, A.C.,Polyak, S.W.,Bruning, J.B.,Lee, K. (deposition date: 2018-12-13, release date: 2019-12-18, Last modification date: 2023-10-11) |
| Primary citation | Lee, K.J.,Tieu, W.,Blanco-Rodriguez, B.,Paparella, A.S.,Yu, J.,Hayes, A.,Feng, J.,Marshall, A.C.,Noll, B.,Milne, R.,Cini, D.,Wilce, M.C.J.,Booker, G.W.,Bruning, J.B.,Polyak, S.W.,Abell, A.D. Sulfonamide-Based Inhibitors of Biotin Protein Ligase as New Antibiotic Leads. Acs Chem.Biol., 14:1990-1997, 2019 Cited by PubMed Abstract: Here, we report the design, synthesis, and evaluation of a series of inhibitors of BPL (BPL), where the central acyl phosphate of the natural intermediate biotinyl-5'-AMP () is replaced by a sulfonamide isostere. Acylsulfamide () and amino sulfonylurea () showed potent inhibitory activity ( = 0.007 ± 0.003 and 0.065 ± 0.03 μM, respectively) and antibacterial activity against ATCC49775 with minimum inhibitory concentrations of 0.25 and 4 μg/mL, respectively. Additionally, the bimolecular interactions between the BPL and inhibitors and were defined by X-ray crystallography and molecular dynamics simulations. The high acidity of the sulfonamide linkers of and likely contributes to the enhanced inhibitory activities by promoting interaction with BPL Lys187. Analogues with alkylsulfamide (), β-ketosulfonamide (), and β-hydroxysulfonamide () isosteres were devoid of significant activity. Binding free energy estimation using computational methods suggests deprotonated and to be the best binders, which is consistent with enzyme assay results. Compound was unstable in whole blood, leading to poor pharmacokinetics. Importantly, has a vastly improved pharmacokinetic profile compared to that of presumably due to the enhanced metabolic stability of the sulfonamide linker moiety. PubMed: 31407891DOI: 10.1021/acschembio.9b00463 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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