Cannariato Marco, Fanunza Riccardo, Zizzi Eric A, Miceli Marcello, Di Benedetto Giacomo, Deriu Marco A, Pallante Lorenzo
PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy.
7HC s.r.l., Rome, Italy.
Front Mol Biosci. 2024 Dec 2;11:1473675. doi: 10.3389/fmolb.2024.1473675. eCollection 2024.
Understanding the intricate interplay between structural features and signal-processing events is crucial for unravelling the mechanisms of biomolecular systems. G protein-coupled receptors (GPCRs), a pervasive protein family in humans, serve a wide spectrum of vital functions. TAS2Rs, a subfamily of GPCRs, play a primary role in recognizing bitter molecules and triggering events leading to the perception of bitterness, a crucial defence mechanism against spoiled or poisonous food. Beyond taste, TAS2Rs function is associated with many diseases as they are expressed in several extra-oral tissues. Given that the precise functioning mechanisms of TAS2R remain poorly understood, this study employed molecular dynamics simulations combined with network-based analysis to investigate local conformational changes and global structural correlations in different states of the receptor. The focus was on the human TAS2R46 bitter taste receptor, recently resolved experimentally, both in the presence and absence of strychnine, a known bitter agonist. The results showed that the ligand-bound state of the receptor exhibited more correlated dynamics compared to the apo state, and the presence of the agonist mediated the allosteric network between two helices (TM3 and TM6) which mainly convey the signal transferring from the extracellular to the intracellular region. By elucidating the hallmarks of the conformational changes and allosteric network of TAS2R46 under varying conditions, this study has enabled the identification of the unique structural and dynamics features of this receptor, thereby establishing a foundation for a more profound characterisation of this intriguing class of receptors.
了解结构特征与信号处理事件之间复杂的相互作用对于揭示生物分子系统的机制至关重要。G蛋白偶联受体（GPCRs）是人类中普遍存在的蛋白质家族，具有广泛的重要功能。TAS2Rs是GPCRs的一个亚家族，在识别苦味分子和触发导致苦味感知的事件中起主要作用，这是一种抵御变质或有毒食物的关键防御机制。除了味觉之外，TAS2Rs的功能还与许多疾病相关，因为它们在几种口腔外组织中表达。鉴于对TAS2R的精确作用机制仍知之甚少，本研究采用分子动力学模拟结合基于网络的分析来研究受体不同状态下的局部构象变化和全局结构相关性。重点是人类TAS2R46苦味受体，最近已通过实验解析，包括存在和不存在已知苦味激动剂士的宁的情况。结果表明，与无配体状态相比，受体的配体结合状态表现出更多的相关动力学，并且激动剂的存在介导了两个螺旋（TM3和TM6）之间的变构网络，这两个螺旋主要传递从细胞外区域到细胞内区域的信号。通过阐明不同条件下TAS2R46的构象变化和变构网络的特征，本研究能够识别该受体独特的结构和动力学特征，从而为更深入地表征这类有趣的受体奠定基础。
