該研究報告了與不同激動劑（即BI167107、hydroxybenzyl isoproterenol和內源性激動劑「腎上腺素」）形成複合物的、完全具有活性的人β2-腎上腺素受體(β2AR)的三個結構。
β2AR是一種「G-蛋白耦合受體」 (GPCR)，後者是很多臨床藥物作為作用目標的普遍存在的膜蛋白。我們對它們與其內源性激動劑相結合的分子過程及其激發效應蛋白的分子過程仍很不了解。
儘管所研究的三種激動劑在化學性質上具有多樣性，但這三種激動劑都能穩定受體中高度相似的活性態。微妙的結構差別讓我們對一個GPCR是怎樣被多種激動劑激發的（這是對藥物開發極為重要的一個現象）有了認識。（生物谷Bioon.com）
生物谷推薦的英文摘要
Nature doi:10.1038/nature12572
Adrenaline-activated structure of β2-adrenoceptor stabilized by an engineered nanobody
Aaron M. Ring，Aashish Manglik，Andrew C. Kruse，Michael D. Enos，William I. Weis，K. Christopher Garcia& Brian K. Kobilka
G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology， yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far， it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists1， 2 or receptor stabilization by mutagenesis3， 4， 5. Many natural agonists such as adrenaline， which activates the β2-adrenoceptor (β2AR)， bind with relatively low affinity， and they are often chemically unstable. Using directed evolution， we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the β2AR， and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active-state human β2AR bound to three chemically distinct agonists： the ultrahigh-affinity agonist BI167107， the high-affinity catecholamine agonist hydroxybenzyl isoproterenol， and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100nM to ~80pM. Overall， the adrenaline-bound receptor structure is similar to the others， but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines， which appears to stabilize the active state of the β2AR and related GPCRs.