Sweet taste perception influences dietary choices and metabolic health. The human sweet taste receptor, a class C G-protein-coupled receptor (GPCR) heterodimer composed of TAS1R2 and TAS1R3 (refs. 1,2), senses a wide range of sweet compounds-including natural sugars, artificial sweeteners and sweet proteins-and affects metabolic regulation beyond taste. However, the lack of three-dimensional structures hinders our understanding of its precise working mechanism. Here we present cryo-electron microscopy structures of the full-length human sweet taste receptor in apo and sucralose-bound states. These structures reveal a distinct asymmetric heterodimer architecture, with sucralose binding exclusively to the Venus flytrap domain of TAS1R2. Combining mutagenesis and molecular dynamics simulations, this work delineates the sweetener-recognition modes in TAS1R2. Structural comparisons further uncover conformational changes upon ligand binding and a unique activation mechanism. These findings illuminate the signal transduction mechanisms of chemosensory receptors in the class C GPCR family and provide the molecular basis for the design of a new generation of sweeteners.

AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and have vital roles in synaptic plasticity, motor coordination, learning and memory1. Whereas extensive structural studies have been conducted on recombinant AMPARs and native calcium-impermeable (CI)-AMPARs alongside their auxiliary proteins2-5, the molecular architecture of native calcium-permeable (CP)-AMPARs has remained undefined. Here, to determine the subunit composition, physiological architecture and gating mechanisms of CP-AMPARs, we visualize these receptors, immunoaffinity purified from rat cerebella, and resolve their structures using cryo-electron microscopy (cryo-EM). Our results indicate that the predominant assembly consists of GluA1 and GluA4 subunits, with the GluA4 subunit occupying the B and D positions, and auxiliary subunits, including transmembrane AMPAR regulatory proteins (TARPs) located at the B' and D' positions, and cornichon homologues (CNIHs) or TARPs located at the A' and C' positions. Furthermore, we resolved the structure of the noelin (NOE1)-GluA1-GluA4 complex, in which NOE1 specifically binds to the GluA4 subunit at the B and D positions. Notably, NOE1 stabilizes the amino-terminal domain layer without affecting gating properties of the receptor. NOE1 contributes to AMPAR function by forming dimeric AMPAR assemblies that are likely to engage in extracellular networks, clustering receptors in synaptic environments and modulating receptor responsiveness to synaptic inputs.

Aromatic rings, also known as arenes, containing two or more adjacent different substituents are ubiquitously found in small-molecule drugs1. Strategies that can rapidly introduce diverse vicinal substituents to readily available precursors would greatly benefit the generation of analogues of biologically active compounds2, which, however, remain challenging to realize so far. The existing approaches for preparing vicinal difunctionalized arenes lack modularity, regioselectivity or generality. Here we report a nickel-catalysed arene vicinal diborylation method that can directly install two chemically differentiated boryl groups in a regioselective and site-selective manner using readily available aryl triflates or chlorides as substrates. This reaction operates under simple and mild conditions and is scalable. It also shows a broad substrate scope and excellent functional group tolerance. Given that each boryl group can be independently transformed into various functional groups, this method offers a modular, regioselective and divergent approach to access diverse vicinal difunctionalized arenes, showing promise for constructing analogue libraries. The combined experimental and computational mechanistic studies reveal a highly unusual reaction pathway, involving the formation of a dearomatized gem-diboryl species and 1,2-boron migration. The site-selectivity and regioselectivity of this reaction are proposed to be controlled by steric interactions of the boryl groups with the nickel catalyst. The mechanistic insights gained in this investigation could have broad implications on developing other boron-mediated functionalization reactions.