Contribution of the CR domain to P-selectin lectin domain allostery by regulating the orientation of the EGF domain.
Contribution of the CR domain to P-selectin lectin domain allostery by regulating the orientation of the EGF domain.
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DOI：
10.1371/journal.pone.0118083
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Long M
中科院分区：
文献类型：
--
作者：
Lü S;Chen S;Mao D;Zhang Y;Long M
p -选择素的变构已被广泛研究，主要集中在Lec和EGF结构域，而CR结构域的作用尚不清楚。本文采用分子动力学模拟（MDS）和同源性建模相结合的方法研究了CR结构域对p -选择素变构的影响。结果表明，CR结构域在p -选择素的变构动力学中起着两种作用。首先，在平衡过程中，CR1结构域倾向于稳定p -选择素的低亲和力，通过抑制EGF弯曲取向的延伸，从S1到S1 '状态的过渡抑制，或通过促进扩展的EGF取向的弯曲，使S2状态的弛豫加速。其次，CR结构域的存在增加了复合物分离前的分子内延伸，增加了在强制解离过程中进行变构位移的时间，延长了键持续时间。这些发现进一步加深了我们对p -选择素的结构-功能关系与CR结构域丰富的微观结构基础的理解。
The allostery of P-selectin has been studied extensively with a focus on the Lec and EGF domains, whereas the contribution of the CR domain remains unclear. Here, molecular dynamics simulations (MDS) combined with homology modeling were preformed to investigate the impact of the CR domain on P-selectin allostery. The results indicated that the CR domain plays a role in the allosteric dynamics of P-selectin in two ways. First, the CR1 domain tends to stabilize the low affinity of P-selectin during the equilibration processes with the transition inhibition from the S1 to S1’ state by restraining the extension of the bent EGF orientation, or with the relaxation acceleration of the S2 state by promoting the bending of the extended EGF orientation. Second, the existence of CR domain increases intramolecular extension prior to complex separation, increasing the time available for the allosteric shift during forced dissociation with a prolonged bond duration. These findings further our understanding of the structure-function relationship of P-selectin with the enriched micro-structural bases of the CR domain.