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The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-Gi signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors. Hydroxyl-carboxylic acid receptor 2 (HCA2) functions as a high-affinity receptor for nicotinic acid (vitamin B3). Here, authors report the cryo-EM structure of the HCA2-Gi complex with the agonist MK-6892 and inactive state crystal structures of mutation stabilized HCA2, to describe the mechanism of HCA2 signaling. [ABSTRACT FROM AUTHOR]

Optical anisotropic (e.g., birefringent) crystals can manipulate the polarization of light and thus are widely applied in modern optical fields. Common birefringent crystals are almost exclusively limited to inorganic oxides with small birefringence. Here, a new 1D hybrid halide perovskite PZPbCl3 (PZ = phenazine) is reported, which consists of perfectly parallel Pb–Cl chains and PZ cations. Remarkably, polarized optical observations show that even a PZPbCl3 crystal with micrometer thickness can modulate the polarized light efficiently. Furthermore, PZPbCl3 exhibits exceptional birefringence up to 0.65@546 nm, which is significantly larger than that of commercial oxide crystals. According to first‐principles calculations and polarizability anisotropy analyses, it is found that this birefringence is mainly ascribed to the linear polymerization of π‐conjugated rings in PZ cations. Due to the rich physical properties and structural diversity of hybrid perovskites, it is believed that the introduction of excellent birefringence into the hybrid perovskites will bring unprecedented opportunities to the future explorations of polarization‐dependent functional materials. [ABSTRACT FROM AUTHOR]

Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and function of β adrenergic receptors (βARs). However, the structure of α adrenergic receptors (αARs) remains to be determined. Here, we report the structure of the human α 2C adrenergic receptor (α 2C AR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α 2C AR-specific D206ECL2-R409ECL3-Y4056.58 network plays a role in determining α 2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α 2C AR is involved in receptor activation. Together, our structure of human α 2C AR-RS79948 provides key insight into the mechanism underlying the α 2 adrenergic receptor activation and subtype selectivity. • Crystal structure of human α 2C AR in complex with RS79948 is solved • A specific loosened helix at the top of TM4 in α 2C AR is involved in receptor activation • Extracellular regions play a role in determining α 2 adrenergic subtype selectivity Chen et al. report the crystal structure of human α 2C AR and the functional experimental results, which indicate that extracellular regions determine α 2 adrenergic subtype selectivity. The structural and functional results provide the molecular explanation for α 2C AR selective ligands and insights to understand GPCR subtype selectivity. [ABSTRACT FROM AUTHOR]

Summary Drugs frequently require interactions with multiple targets—via a process known as polypharmacology—to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT 2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT 2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT 2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT 2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs. [ABSTRACT FROM AUTHOR]

Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G i , as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role. • 3D structures of CB2-AM12033-G i , CB1-AM841-G i , and CB2-AM12033 are determined • Structural evidence of G protein selectivity by CB1 and CB2 is identified • MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1 • Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered Structure and simulations of cannabinoid receptors CB2 and CB1 in their inactive, active-like, and activated signaling states reveal residue differences that may provide G protein selectivity, the distinct binding behavior of CB2 agonists in CB2 and CB1, as well as evidence for modulation of CB1 by cholesterol binding. [ABSTRACT FROM AUTHOR]

Summary The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system. Graphical Abstract Highlights • Crystal structure of human CB2 in complex with antagonist AM10257 is determined • A high degree of conformational similarity with the agonist-bound CB1 is uncovered • The yin-yang relationship of CB2 and CB1 will facilitate the design of selective drugs The structure of the human cannabinoid receptor CB2 reveals how small molecules affect CB2 differently than CB1 and point to principles that could inform rational and selective drug design. [ABSTRACT FROM AUTHOR]

Summary Cannabinoid receptor 1 (CB 1 ) is the principal target of Δ 9 -tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB 1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB 1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB 1 -AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB 1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB 1 and provides new opportunities for the design of next-generation CB 1 -targeting pharmaceuticals. [ABSTRACT FROM AUTHOR]