| 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
|
| リソース情報 |
| ヒト・動物細胞 |
MC3T3-E1(RCB1126) |
