Exploration of inositol 1,4,5-trisphosphate (IP 3 ) regulated dynamics of N-terminal domain of IP 3 receptor reveals early phase molecular events during receptor activation
Exploration of inositol 1,4,5-trisphosphate (IP 3 ) regulated dynamics of N-terminal domain of IP 3 receptor reveals early phase molecular events during receptor activation
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肌醇 1,4,5-三磷酸 (IP 3 ) 调节 IP 3 受体 N 端结构域动力学的探索揭示了受体激活过程中的早期分子事件
DOI：
10.1101/404020
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Chandran A
中科院分区：
文献类型：
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作者：
Chandran A
肌醇1，4，5-三磷酸（IP 3）与IP 3受体（IP 3R）N端（NT）的结合，可使IP 3结合核心（IBC）100 nm处的Ca ~（2+）通道开放。然而，IP 3结合的精确机制和NT中的相关结构域动力学是IP 3R活化的核心，仍然未知。我们的全原子分子动力学（MD）模拟概括的特征扭曲运动的抑制结构域（SD），并揭示相关的“蛤蜊关闭”的动态IBC与IP 3结合，补充现有的建议IP 3R激活机制。我们的研究进一步揭示了存在的域间动态相关的NT和建立SD是关键的构象动力学的IBC。此外，涉及SD-IBC界面处的Glu 283-Arg 54-Asp 444的三方相互作用似乎对IP 3R活化至关重要。有趣的是，在亚微秒长的模拟过程中，我们观察到Arg 269在IP 3的第一个和第五个磷酸基团之间发生了SD依赖的氢键翻转。这似乎在确定存在/不存在SD时IBC的IP 3结合亲和力中起主要作用。因此，我们的研究提供了原子的细节，早期分子事件发生在NT期间和之后的IP 3绑定，导致通道门控。
Inositol 1, 4, 5-trisphosphate (IP3) binding at the N-terminus (NT) of IP3receptor (IP3R) allosterically triggers the opening of a Ca2+-conducting pore located ~100 Å away from the IP3-binding core (IBC). However, the precise mechanism of IP3binding and correlated domain dynamics in the NT that are central to the IP3R activation, remains unknown. Our all-atom molecular dynamics (MD) simulations recapitulate the characteristic twist motion of the suppressor domain (SD) and reveal correlated ‘clam closure’ dynamics of IBC with IP3-binding, complementing existing suggestions on IP3R activation mechanism. Our study further reveals the existence of inter-domain dynamic correlation in the NT and establishes the SD to be critical for the conformational dynamics of IBC. Also, a tripartite interaction involving Glu283-Arg54-Asp444 at the SD – IBC interface seemed critical for IP3R activation. Intriguingly, during the sub-microsecond long simulation, we observed Arg269 undergoing an SD-dependent flipping of hydrogen bonding between the first and fifth phosphate groups of IP3. This seems to play a major role in determining the IP3binding affinity of IBC in the presence/absence of the SD. Our study thus provides atomistic details of early molecular events occurring within the NT during and following IP3binding that lead to channel gating.