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A(2A) and A(2B) adenosine receptors: The extracellular loop 2 determines high (A(2A)) or low affinity (A(2B)) for adenosine

机译:(2a)和a(2b)腺苷受体:细胞外环2确定腺苷的高(2a))或低亲和力(a(2b))

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A(2A) and A(2B) adenosine receptors (ARs) are closely related G protein-coupled receptor subtypes, which represent important (potential) drug targets. Despite their almost identical binding sites for adenosine, A(2A)ARs are activated by low (nanomolar) adenosine concentrations, while A(2B)ARs require micromolar concentrations. In the present study, we exchanged the extracellular loop 2 (ECL2) of the human A(2A)AR for that of the A(2B)AR. The resulting chimeric A(2A)(ECL2-A(2B))AR was investigated in radioligand binding and cAMP accumulation assays in comparison to the wildtype A(2A)AR. While the ribose-modified adenosine analog N-ethylcarboxamidoadenosine (NECA) and its 2-substituted derivative CGS-21680 did not exhibit significant changes, adenosine showed dramatically reduced potency and affinity for the A(2A)(ECL2-A(2B))AR mutant displaying similarly low potency as for the wt A(2B)AR. Supervised molecular dynamics simulation studies predicted a meta-binding site with high affinity for adenosine, but not for NECA, which may contribute to the observed effects.
机译:(2a)和a(2b)腺苷受体(Ars)是密切相关的g蛋白偶联受体亚型,其代表重要的(潜在)药物靶标。尽管其几乎相同的腺苷结合位点,但是(2a)ars由低(纳米摩尔)腺苷浓度激活,而a(2b)ars需要微摩尔浓度。在本研究中,我们将人A(2A)AR的细胞外环2(ECL2)交换为A(2B)AR。与野生型A(2a)Ar相比,研究了所得嵌合A(2a)(ECL2-A(2b))Ar。虽然核糖改性的腺苷类似N-乙基羧酰胺纳米葡萄酒(NECA)及其2取代的衍生物CGS-21680没有表现出显着的变化,但腺苷显示出对A(2a)(ECL2-A(2b))AR的效力和亲和力显着降低突变体显示与WT a(2b)AR类似的效力。监督分子动力学模拟研究预测了对腺苷具有高亲和力的元结合位点,但不适用于NECA,这可能有助于观察到的效果。

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