分类: 药物科学 >> 结构生物学 提交时间: 2024-04-17
摘要: The adenosine A3 receptor (A3AR) belongs to a subfamily of G protein-coupled receptors and is an important therapeutic target for conditions including inflammation and cancer. The clinical compounds CF101 and CF102 are potent and selective A3AR agonists, but the structural basis of their recognition was unknown. Here we present the cryogenic electron microscopy structures of the full-length human A3AR bound to CF101 and CF102 at 3.3-3.2 Å resolution in complex with heterotrimeric Gi protein. These agonists bind within the orthosteric pocket, with their adenine components engaging in conserved interactions while their substituted 3-iodobenzyl groups exhibit different orientations. Swapping extracellular loop 3 (ECL3) of A3AR onto other adenosine receptor subtypes enabled CF101/CF102 binding and receptor activaton, and mutations in key residues, including His3.37, Ser5.42 and Ser6.52 that form a unique subpocket in A3AR, abolished receptor activation, highlighting these structural elements are critical for ligand selectivity. Compared to inactive A2AAR, the A3AR structures reveal conserved mechanism of receptor activation, including an outward shift of TM6. These structures provide key insights into molecular recognition and signaling mechanisms of A3AR, which should aid rational design of subtype-selective ligands targeting this important class of adenosine receptors.
分类: 心理学 >> 认知心理学 分类: 心理学 >> 心理统计 提交时间: 2024-04-16
摘要: 认知建模近年来在科学心理学获得广泛应用,而模型比较是认知建模中关键的一环:研究者需要通过模型比较来选择出最优模型,才能进行后续的假设检验或潜变量推断。模型比较不仅要考虑模型对数据的拟合(平衡过拟合与欠拟合),也需要考虑参数数据和数学形式的复杂度。然而,模型比较指标众多,纷繁复杂。将认知建模常用的模型比较的指标分为三大类,并介绍了其计算方法及优劣,包括拟合优度指标(包括平均平方误差、决定系数、RUC曲线等)、基于交叉验证的指标(包括AIC、DIC等)和基于边际似然的指标。结合正交Go /No-Go范式下的数据,展示各指标在R语言中如何实现。在此基础上,探讨各指标的适用情境,介绍模型平均等模型比较的新思路。