The interplay of receptor dynamics and ligand residence time upon ligand efficacy at adenosine receptors (C02)

受体动力学和配体停留时间对腺苷受体（CO2）上配体功效的相互作用

• 批准号: 279227385
• 金额: --
• 依托单位: Institut für Molekulare Zellbiologie
• 依托单位国家: 德国
• 项目类别: CRC/Transregios
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/279227385?language=en
• 关键词: interplay; receptor; dynamics; ligand; residence

The molecular details leading to increased ligand residence time are currently insufficiently understood. The major question within this project will be to address conformational dynamic of a receptor in relation to ligand binding using FRET-microscopy with high kinetic resolution in living cells. Using adenosine receptors, we will: I) Study the role of the extracellular loop 2 in ligand binding kinetics; II) Compare the low ligand affinity A2B receptor to the high affinity A1 and A2A receptors; III) Investigate dynamic ligand binding in relation to the conformational dynamics of the H251A mutation at the A1 receptor; IV) Study the influence of G-proteins in receptor dynamics and receptor localization; V) Investigate the role of allosteric modulators in residence time and signaling using PD 81,723 as prototype; VI) Adapt the system to 96-well plates for faster throughput.

导致配体停留时间增加的分子细节目前还不充分了解。在这个项目中的主要问题将是解决构象动态的受体与配体结合使用FRET显微镜在活细胞中具有高动力学分辨率。利用腺苷受体，我们将：I）研究细胞外环2在配体结合动力学中的作用; II）比较低配体亲和力A2 B受体与高亲和力A1和A2 A受体; III）研究与A1受体H251 A突变的构象动力学相关的动态配体结合; IV）研究G蛋白在受体动力学和受体定位中的影响; V）使用PD 81，723作为原型研究别构调节剂在停留时间和信号传导中的作用; VI）使系统适应96孔板以获得更快的通量。