Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.
Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.
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头域的固有动态与 P2X4 受体的 ATP 识别相关：从分子模拟中获得的见解。
DOI：
10.1371/journal.pone.0097528
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Huang LD;Fan YZ;Tian Y;Yang Y;Liu Y;Wang J;Zhao WS;Zhou WC;Cheng XY;Cao P;Lu XY;Yu Y
P2 X受体是一种ATP门控离子通道，参与多种生理功能，研究P2 X受体的ATP识别（AR）特性将有助于开发治疗疼痛、炎症、膀胱功能障碍和骨质疏松症的新药物。斑马鱼P2 X4（zfP 2X 4）受体的最新晶体结构揭示了位于zfP 2X 4受体的亚基界面处的大的ATP结合口袋（ABP），其被显著的碱性残基簇占据以识别ATP的三磷酸部分。使用工程亲和标记和分子建模，ABP内至少有三个位点（S1，S2和S3）已被确定能够识别ATP的腺嘌呤环，这意味着ABP中至少存在三种不同的AR模式。zfP 2X 4的开放晶体结构证实了三种AR模式之一（称为AR 1），其中ATP的腺嘌呤环被埋在S1位点，而三磷酸部分与成簇的碱性残基相互作用。为什么ABP的架构有利于AR 1而不是其他两种AR模式仍然没有被探索。在这里，我们研究的潜在作用的固有动力学的头域，一个域参与ABP的形成，在AR决定P2 X4受体。在silico对接和结合自由能计算显示了三个不同的AR模式的可比字符。头域的内在动力学，特别是向下运动有利于ABP对AR 1的偏好，而不是AR 2和AR 3。沿着头部结构域的向下运动，环139 -146和环169 -183的闭合运动以及K70、K72、R298和R143的结构重排使ABP能够区分AR 1和其他AR模式。我们的观察表明，头部结构域的动力学在确定AR的P2 X4受体的重要作用，允许评估的新策略，旨在开发特定的阻滞剂/变构调节剂，通过防止与AR和通道激活的P2 X4受体相关的头部结构域的动力学。
P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139–146 and loop169–183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.
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影响因子：
11.4
作者：
Jiang, Ruotian;Taly, Antoine;Grutter, Thomas
通讯作者：
Grutter, Thomas
影响因子：
64.8
作者：
Gu, JGG;MacDermott, AB
通讯作者：
MacDermott, AB
DOI：
10.1073/pnas.1102170108
发表时间：
2011-05-31
影响因子：
11.1
作者：
Jiang, Ruotian;Lemoine, Damien;Grutter, Thomas
通讯作者：
Grutter, Thomas
影响因子：
11.4
作者：
CAVARELLI, J;ERIANI, G;MORAS, D
通讯作者：
MORAS, D
DOI：
10.1056/nejmra1205750
发表时间：
2012-12-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eltzschig HK;Sitkovsky MV;Robson SC
通讯作者：
Robson SC