资源环境科技发展态势分析平台

The beta(1)-adrenoceptor (beta(1)AR) is a G-protein-coupled receptor (GPCR) that couples(1)to the heterotrimeric G protein G(s). G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of beta-arrestin 1 (beta arr1, also known as arrestin 2), which displaces G(s)and induces signalling through the MAP kinase pathway(2). The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism(3)-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects(4). To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the beta(1)AR-beta arr1 complex in lipid nanodiscs bound to the biased agonist formoterol(5), and the crystal structure of formoterol-bound beta(1)AR coupled to the G-protein-mimetic nanobody(6)Nb80. beta arr1 couples to beta(1)AR in a manner distinct to that(7)of G(s)coupling to beta(2)AR-the finger loop of beta arr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal alpha 5 helix of G(s). The conformation of the finger loop in beta arr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin(8). beta(1)AR coupled to beta arr1 shows considerable differences in structure compared with beta(1)AR 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 beta(1)AR, and find that formoterol has a lower affinity for the beta(1)AR-beta arr1 complex than for the beta(1)AR-G(s)complex. The structural differences between these complexes of beta(1)AR provide a foundation for the design of small molecules that could bias signalling in the beta-adrenoceptors.

A cryo-electron microscopy structure of the beta 1-adrenoceptor coupled to beta-arrestin 1 and activated by the biased agonist formoterol, as well as the crystal structure of a related formoterol-bound adrenoreceptor, provide insights into biased signalling in these systems.

Room-temperature electrical switching of a topological antiferromagnetic state in polycrystalline Mn3Sn thin films is demonstrated using the same protocol as that used for conventional ferromagnetic metals.

Electrical manipulation of phenomena generated by nontrivial band topology is essential for the development of next-generation technology using topological protection. A Weyl semimetal is a three-dimensional gapless system that hosts Weyl fermions as low-energy quasiparticles(1-4). It has various exotic properties, such as a large anomalous Hall effect (AHE) and chiral anomaly, which are robust owing to the topologically protected Weyl nodes(1-16). To manipulate such phenomena, a magnetic version of Weyl semimetals would be useful for controlling the locations of Weyl nodes in the Brillouin zone. Moreover, electrical manipulation of antiferromagnetic Weyl metals would facilitate the use of antiferromagnetic spintronics to realize high-density devices with ultrafast operation(17,18). However, electrical control of a Weyl metal has not yet been reported. Here we demonstrate the electrical switching of a topological antiferromagnetic state and its detection by the AHE at room temperature in a polycrystalline thin film(19) of the antiferromagnetic Weyl metal Mn3Sn9,10,12,20, which exhibits zero-field AHE. Using bilayer devices composed of Mn3Sn and nonmagnetic metals, we find that an electrical current density of about 10(10) to 10(11) amperes per square metre induces magnetic switching in the nonmagnetic metals, with a large change in Hall voltage. In addition, the current polarity along the bias field and the sign of the spin Hall angle of the nonmagnetic metals-positive for Pt (ref. (21)), close to 0 for Cu and negative for W (ref. (22))-determines the sign of the Hall voltage. Notably, the electrical switching in the antiferromagnet is achieved with the same protocol as that used for ferromagnetic metals(23,24). Our results may lead to further scientific and technological advances in topological magnetism and antiferromagnetic spintronics.