論文 - 詳細
| RRC ID | 42801 |
|---|---|
| 著者 | Boilard E, Rouault M, Surrel F, Le Calvez C, Bezzine S, Singer A, Gelb MH, Lambeau G. |
| タイトル | Secreted phospholipase A2 inhibitors are also potent blockers of binding to the M-type receptor. |
| ジャーナル | Biochemistry |
| Abstract |
Mammalian secreted phospholipases A(2) (sPLA(2)s) constitute a family of structurally related enzymes that are likely to play numerous biological roles because of their phospholipid hydrolyzing activity and binding to soluble and membrane-bound proteins, including the M-type receptor. Over the past decade, a number of competitive inhibitors have been developed against the inflammatory-type human group IIA (hGIIA) sPLA(2) with the aim of specifically blocking its catalytic activity and pathophysiological functions. The fact that many of these inhibitors, including the indole analogue Me-Indoxam, inhibit several other sPLA(2)s that bind to the M-type receptor prompted us to investigate the impact of Me-Indoxam and other inhibitors on the sPLA(2)-receptor interaction. By using a Ca(2+) loop mutant derived from a venom sPLA(2) which is insensitive to hGIIA inhibitors but still binds to the M-type receptor, we demonstrate that Me-Indoxam dramatically decreases the affinity of various sPLA(2)s for the receptor, yet an sPLA(2)-Me-Indoxam-receptor complex can form at very high sPLA(2) concentrations. Me-Indoxam inhibits the binding of iodinated mouse sPLA(2)s to the mouse M-type receptor expressed on live cells but also enhances binding of sPLA(2) to phospholipids. Because Me-Indoxam and other competitive inhibitors protrude out of the sPLA(2) catalytic groove, it is likely that the inhibitors interfere with the sPLA(2)-receptor interaction by steric hindrance and to different extents that depend on the type of sPLA(2) and inhibitor. Our finding suggests that the various anti-inflammatory therapeutic effects of sPLA(2) inhibitors may be due not only to inhibition of enzymatic activity but also to modulation of binding of sPLA(2) to the M-type receptor or other as yet unknown protein targets. |
| 巻・号 | 45(44) |
| ページ | 13203-18 |
| 公開日 | 2006-11-7 |
| DOI | 10.1021/bi061376d |
| PMID | 17073442 |
| MeSH | Animals Binding Sites Carbamates / pharmacology Catalysis Enzyme Inhibitors / pharmacology* Indolizines / pharmacology Membrane Proteins / metabolism* Mice Models, Molecular Phospholipases A / antagonists & inhibitors* Phospholipases A / metabolism Phospholipases A2 Rabbits Snake Venoms / enzymology |
| IF | 2.865 |
| 引用数 | 24 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 9 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | MC3T3-E1(RCB1126) |