科學家解析β-arrestin與福莫特羅結合β1-腎上腺素受體的結構
作者：
小柯機器人發布時間：2020/6/18 22:12:29
英國MRC分子生物學實驗室Christopher G. Tate及其研究小組闡明了β-arrestin（βarr1）與福莫特羅結合β1-腎上腺素受體（β1AR）的分子基礎。 相關論文於2020年6月17日在線發表在《自然》雜誌上。
為了解抑制蛋白偶聯的分子基礎，研究人員解析了與偏好性激動劑福莫特羅結合的脂質納米盤中β1AR–βarr1複合物的冷凍電鏡結構，以及福莫特羅結合的β1AR與G蛋白模擬納米抗體Nb80的晶體結構。βarr1以與Gs耦合至β2AR Gs7不同的方式耦合至β1AR，βarr1的指環在細胞內表面上的裂隙較窄，並且與Gs C端的α5螺旋相比更靠近受體的跨膜螺旋H7。βarr1中指環的構象與視紫紅質抑制蛋白中指環與視紫紅質偶聯時所採用的構象不同。和Nb80偶聯的β1AR相比，與βarr1偶聯的β1AR在結構上存在顯著差異，包括細胞外環3的向內運動以及H5和H6的胞質末端。
研究人員觀察到福莫特羅與β1AR正構結合位點H5中兩個絲氨酸殘基之間的相互作用減弱，福莫特羅對β1AR-βarr1複合物的親和力比對β1AR-Gs複合物的親和力低。β1AR的這些複合物之間的結構差異為設計可能偏向β-腎上腺素受體信號傳導的小分子提供了基礎。
研究人員表示，β1AR是與異三聚體G蛋白Gs偶聯的G蛋白偶聯受體（GPCR）。GPCR激酶（GRKs）受體C末端的磷酸化與β-arrestin1（也稱為抑制蛋白）偶聯可終止G蛋白介導的信號傳導，從而取代Gs並通過MAP誘導信號傳導激酶途徑。合成激動劑優先通過G蛋白或抑制蛋白誘導信號轉導的能力（又稱偏好性激動劑）而在藥物開發中很重要，因為治療效果可能僅來自一個信號級聯反應，而另一種途徑可能介導不良副作用。
附：英文原文
Title: Molecular basis of β-arrestin coupling to formoterol-bound β 1 -adrenoceptor
Author: Yang Lee, Tony Warne, Rony Nehm, Shubhi Pandey, Hemlata Dwivedi-Agnihotri, Madhu Chaturvedi, Patricia C. Edwards, Javier Garca-Nafra, Andrew G. W. Leslie, Arun K. Shukla, Christopher G. Tate
Issue&Volume: 2020-06-17
Abstract: The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins—known as biased agonism3—is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR–βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR—the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR–βarr1 complex than for the β1AR–Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors.
DOI: 10.1038/s41586-020-2419-1
Source: https://www.nature.com/articles/s41586-020-2419-1