Martí-Solano Maria, Sanz Ferran, Pastor Manuel, Selent Jana
Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
PLoS One. 2014 Oct 14;9(10):e109312. doi: 10.1371/journal.pone.0109312. eCollection 2014.
Functional selectivity is a property of G protein-coupled receptors that allows them to preferentially couple to particular signaling partners upon binding of biased agonists. Publication of the X-ray crystal structure of serotonergic 5-HT1B and 5-HT2B receptors in complex with ergotamine, a drug capable of activating G protein coupling and β-arrestin signaling at the 5-HT1B receptor but clearly favoring β-arrestin over G protein coupling at the 5-HT2B subtype, has recently provided structural insight into this phenomenon. In particular, these structures highlight the importance of specific residues, also called micro-switches, for differential receptor activation. In our work, we apply classical molecular dynamics simulations and enhanced sampling approaches to analyze the behavior of these micro-switches and their impact on the stabilization of particular receptor conformational states. Our analysis shows that differences in the conformational freedom of helix 6 between both receptors could explain their different G protein-coupling capacity. In particular, as compared to the 5-HT1B receptor, helix 6 movement in the 5-HT2B receptor can be constrained by two different mechanisms. On the one hand, an anchoring effect of ergotamine, which shows an increased capacity to interact with the extracellular part of helices 5 and 6 and stabilize them, hinders activation of a hydrophobic connector region at the center of the receptor. On the other hand, this connector region in an inactive conformation is further stabilized by unconserved contacts extending to the intracellular part of the 5-HT2B receptor, which hamper opening of the G protein binding site. This work highlights the importance of considering receptor capacity to adopt different conformational states from a dynamic perspective in order to underpin the structural basis of functional selectivity.
功能选择性是G蛋白偶联受体的一种特性，使得它们在结合偏向性激动剂时能够优先与特定的信号转导伙伴偶联。血清素能5-HT1B和5-HT2B受体与麦角胺复合物的X射线晶体结构已发表，麦角胺是一种药物，它能够激活5-HT1B受体的G蛋白偶联和β-抑制蛋白信号传导，但在5-HT2B亚型中明显更倾向于β-抑制蛋白而非G蛋白偶联，这一成果最近为这一现象提供了结构上的见解。特别是，这些结构突出了特定残基（也称为微开关）对于差异性受体激活的重要性。在我们的工作中，我们应用经典分子动力学模拟和增强采样方法来分析这些微开关的行为及其对特定受体构象状态稳定化的影响。我们的分析表明，两种受体之间螺旋6构象自由度的差异可以解释它们不同的G蛋白偶联能力。特别是，与5-HT1B受体相比，5-HT2B受体中螺旋6的移动可以通过两种不同机制受到限制。一方面，麦角胺的锚定效应，它显示出与螺旋5和6的细胞外部分相互作用并使其稳定的能力增强，阻碍了受体中心疏水连接区域的激活。另一方面，处于非活性构象的这个连接区域通过延伸到5-HT2B受体细胞内部分的非保守接触进一步稳定，这阻碍了G蛋白结合位点的开放。这项工作强调了从动态角度考虑受体采用不同构象状态的能力的重要性，以便为功能选择性的结构基础提供支撑。
