Structural Basis for the Inhibitor and Substrate Specificity of the Unique Fph Serine Hydrolases of Staphylococcus aureus
文献类型：期刊论文
| 作者 | Fellner, Matthias4; Lentz, Christian S.1,2,3; Jamieson, Sam A.4; Brewster, Jodi L.4; Chen, Linhai1,5 ; Bogyo, Matthew1; Mace, Peter D.4
|
| 刊名 | ACS INFECTIOUS DISEASES
 |
| 出版日期 | 2020-10-09 |
| 卷号 | 6期号:10页码:2771-2782 |
| 关键词 | Staphylococcus aureus activity-based probe serine hydrolases acyl inhibitor |
| ISSN号 | 2373-8227 |
| DOI | 10.1021/acsinfecdis.0c00503 |
| 文献子类 | Article |
| 英文摘要 | Staphylococcus aureus is a prevalent bacterial pathogen in both community and hospital settings, and its treatment is made particularly difficult by resilience within biofilms. Within this niche, serine hydrolase enzymes play a key role in generating and maintaining the biofilm matrix. Activity-based profiling has previously identified a family of serine hydrolases, designated fluorophosphonate-binding hydrolases (Fph's), some of which contribute to the virulence of S. aureus in vivo. These 10 Fph proteins have limited annotation and have few, if any, characterized bacterial or mammalian homologues. This suggests unique hydrolase functions even within bacterial species. Here we report structures of one of the most abundant Fph family members, FphF. Our structures capture FphF alone, covalently bound to a substrate analogue and bound to small molecule inhibitors that occupy the hydrophobic substrate-binding pocket. In line with these findings, we show that FphF has promiscuous esterase activity toward hydrophobic lipid substrates. We present docking studies that characterize interactions of inhibitors and substrates within the active site environment, which can be extended to other Fph family members. Comparison of FphF to other esterases and the wider Fph protein family suggest that FphF forms a new esterase subfamily. Our data suggest that other Fph enzymes, including the virulence factor FphB, are likely to have more restricted substrate profiles than FphF. This work demonstrates a clear molecular rationale for the specificity of fluorophosphonate probes that target FphF and provides a structural template for the design of enhanced probes and inhibitors of the Fph family of serine hydrolases. |
| WOS关键词 | S-FORMYLGLUTATHIONE HYDROLASE ; MACROMOLECULAR CRYSTALLOGRAPHY COMMUNITIES ; CRYSTAL-STRUCTURE ; PSEUDOMONAS-AERUGINOSA ; ESTERASE ; TOOL ; RESISTANCE ; EPIDEMIOLOGY ; PROTEIN ; SYSTEM |
| WOS研究方向 | Pharmacology & Pharmacy ; Infectious Diseases |
| 语种 | 英语 |
| WOS记录号 | WOS:000580584600021 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309407]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Fellner, Matthias |
| 作者单位 | 1.Stanford Univ, Pathol Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA; 2.UiT Arctic Univ Norway, Dept Med Biol, Ctr New Antibacterial Strategies CANS, N-9037 Tromso, Norway; 3.UiT Arctic Univ Norway, Dept Med Biol, Res Grp Host Microbe Interact, N-9037 Tromso, Norway; 4.Univ Otago, Sch Biomed Sci, Biochem Dept, Dunedin 9054, New Zealand; 5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Fellner, Matthias,Lentz, Christian S.,Jamieson, Sam A.,et al. Structural Basis for the Inhibitor and Substrate Specificity of the Unique Fph Serine Hydrolases of Staphylococcus aureus[J]. ACS INFECTIOUS DISEASES,2020,6(10):2771-2782. |
| APA | Fellner, Matthias.,Lentz, Christian S..,Jamieson, Sam A..,Brewster, Jodi L..,Chen, Linhai.,...&Mace, Peter D..(2020).Structural Basis for the Inhibitor and Substrate Specificity of the Unique Fph Serine Hydrolases of Staphylococcus aureus.ACS INFECTIOUS DISEASES,6(10),2771-2782. |
| MLA | Fellner, Matthias,et al."Structural Basis for the Inhibitor and Substrate Specificity of the Unique Fph Serine Hydrolases of Staphylococcus aureus".ACS INFECTIOUS DISEASES 6.10(2020):2771-2782. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。