Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β₁AR and β₂AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β₁AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β₁AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β₁AR and β₂AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.

β 肾上腺素能受体 (βARs) 介导对交感神经系统释放的儿茶酚胺肾上腺素和去甲肾上腺素的生理反应。虽然激素肾上腺素以相似的亲和力结合 β ₁ AR 和 β _{2 AR，但较小的神经递质去甲肾上腺素对 β 1} AR的选择性大约为十倍。为了解这种重要生理选择性的结构基础，我们解析了与拮抗剂卡拉唑和不同激动剂（包括去甲肾上腺素、肾上腺素和 BI-167107）结合的人 β _{1 AR 的晶体结构。}结构比较表明，β ₁ AR 和 β _{2之间的儿茶酚胺结合袋是相同的}AR，但细胞外前庭具有不同的形状和静电特性。元动力学模拟和诱变研究表明，这些差异会影响去甲肾上腺素进入正构袋的路径，并导致不同的结合率，从而导致不同的亲和力。