Synthetic partial agonists reveal key steps in IP3 receptor activation.
Synthetic partial agonists reveal key steps in IP3 receptor activation.
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DOI：
10.1038/nchembio.195
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发表时间：
2009-09
影响因子：
14.8
通讯作者：
Taylor, Colin W.
中科院分区：
文献类型：
--
作者：
Rossi, Ana M.;Riley, Andrew M.;Tovey, Stephen C.;Rahman, Taufiq;Dellis, Olivier;Taylor, Emily J. A.;Veresov, Valery G.;Potter, Barry V. L.;Taylor, Colin W.
肌醇1，4，5-三磷酸受体（IP3R）是细胞内普遍存在的钙通道。IP3结合到靠近N-末端的IP3结合核心（IBC）引发构象变化，导致孔的打开。机制尚未解决。我们合成了2-O-修饰的IP3类似物，它们是IP3R的部分激动剂。它们在与IBC的相互作用方面类似于IP3，但它们在重新排列IBC和N-末端抑制结构域（SD）之间的关系方面不如IP3有效，并且它们以较慢的速率打开通道。在SD中具有占据与部分激动剂的2-O-取代基相似的位置的突变的IP3R具有降低的开放概率，这对于完全和部分激动剂是相似的。因此，来自配体或SD的大体积或带电取代基阻断IBC和SD的强制性偶联。配体结合的Δ G分析表明，IP3被IBC识别，然后构象变化完全通过SD传播到孔。
Inositol 1,4,5-trisphosphate receptors (IP3R) are ubiquitous intracellular Ca2+ channels. IP3binding to the IP3-binding core (IBC) near the N-terminal initiates conformational changes that lead to opening of a pore. The mechanisms are unresolved. We synthesized 2-O-modified IP3 analogues that are partial agonists of IP3R. These are like IP3 in their interactions with the IBC, but they are less effective than IP3 in rearranging the relationship between the IBC and N-terminal suppressor domain (SD), and they open the channel at slower rates. IP3R with a mutation in the SD occupying a position similar to the 2-O-substituent of the partial agonists has a reduced open probability that is similar for full and partial agonists. Bulky or charged substituents from either the ligand or SD therefore block obligatory coupling of the IBC and SD. Analysis of ΔG for ligand binding shows that IP3 is recognised by the IBC and conformational changes then propagate entirely via the SD to the pore.
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