6NDL

Crystal structure of Staphylococcus aureus biotin protein ligase in complex with a sulfonamide inhibitor

6NDL の概要

• エントリーDOI: 10.2210/pdb6ndl/pdb
• 分子名称: 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)
• 機能のキーワード: bpl inhibitor, sulfonamide analogue, amino sulfonylurea, antibiotic, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 39058.99

構造登録者

Marshall, A.C.,Polyak, S.W.,Bruning, J.B.,Lee, K. (登録日: 2018-12-13, 公開日: 2019-12-18, 最終更新日: 2023-10-11)

主引用文献

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

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: 31407891
DOI: 10.1021/acschembio.9b00463

実験手法

X-RAY DIFFRACTION (2 Å)