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•Phylogenetic tree of spike proteins reveals major groups of coronaviruses.•Furin cleavage sites at spike S1/S2 are common in coronaviruses.•Furin cleavage sites at spike S1/S2 ...naturally occurred independently for multiple times in coronaviruses.
The spike protein is a focused target of COVID-19, a pandemic caused by SARS-CoV-2. A 12-nt insertion at S1/S2 in the spike coding sequence yields a furin cleavage site, which raised controversy views on origin of the virus. Here we analyzed the phylogenetic relationships of coronavirus spike proteins and mapped furin recognition motif on the tree. Furin cleavage sites occurred independently for multiple times in the evolution of the coronavirus family, supporting the natural occurring hypothesis of SARS-CoV-2.
MXene is a generic name for a large family of two-dimensional transition metal carbides or nitrides, which show great promise in the field of transparent supercapacitors. However, the manufacturing ...of supercapacitor electrodes with a high charge storage capacity and desirable transmittance is a challenging task. Herein, a low-cost, large-scale, and rapid preparation of flexible and transparent MXene films via inkjet printing is reported. The MXene films realized the sheet resistance (R s) of 1.66 ± 0.16 MΩ sq–1 to 1.47 ± 0.1 kΩ sq–1 at the transmissivity of 87–24% (λ = 550 nm), respectively, corresponding to the figure of merit (the ratio of electronic to optical conductivity, σDC/σOP) of ∼0.0012 to 0.13. Furthermore, the potential of inkjet-printed transparent MXene films in transparent supercapacitors was assessed by electrochemical characterization. The MXene film, with a transmittance of 24%, exhibited a superior areal capacitance of 887.5 μF cm–2 and retained 85% of the initial capacitance after 10,000 charge/discharge cycles at the scan rate of 10 mV s–1. Interestingly, the areal capacitance (192 μF cm–2) of an assembled symmetric MXene transparent supercapacitor, with a high transmittance of 73%, still surpasses the performance of previously reported graphene and single-walled carbon nanotube (SWCNT)-based transparent electrodes. The convenient manufacturing and superior electrochemical performance of inkjet-printed flexible and transparent MXene films widen the application horizon of this strategy for flexible energy storage devices.
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 Gi, 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.
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•3D structures of CB2-AM12033-Gi, CB1-AM841-Gi, 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.
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.
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•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.
Adrenergic receptors are G protein-coupled receptors for epinephrine and norepinephrine. They are targets of many drugs for various conditions, including treatment of hypertension, hypotension, and ...asthma. Adrenergic receptors are intensively studied in structural biology, displayed for binding poses of different types of ligands. Here, we summarized molecular mechanisms of ligand recognition and receptor activation exhibited by structure. We also reviewed recent advances in structure-based ligand discovery against adrenergic receptors.
The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Here we report two agonist-bound crystal ...structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1-agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a 'twin toggle switch' of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several ...psychiatric disorders
. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G
protein
, but it is unclear how GPR52 and G
couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G
-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52
. A fully active state is achieved when G
is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.
As one of the most successful therapeutic target families, G protein-coupled receptors (GPCRs) have experienced a transformation from random ligand screening to knowledge-driven drug design. We are ...eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace. This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
Taste sensing is a sophisticated chemosensory process, and bitter taste perception is mediated by type 2 taste receptors (TAS2Rs), or class T G protein–coupled receptors. Understanding the detailed ...molecular mechanisms behind taste sensation is hindered by a lack of experimental receptor structures. Here, we report the cryo–electron microscopy structures of human TAS2R46 complexed with chimeric mini–G protein gustducin, in both strychnine-bound and apo forms. Several features of TAS2R46 are disclosed, including distinct receptor structures that compare with known GPCRs, a new “toggle switch,” activation-related motifs, and precoupling with mini–G protein gustducin. Furthermore, the dynamic extracellular and more-static intracellular parts of TAS2R46 suggest possible diverse ligand-recognition and activation processes. This study provides a basis for further exploration of other bitter taste receptors and their therapeutic applications.
Tasting bitter
Bitter, sweet, and umami tastes are transduced by G protein–coupled receptors (GPCRs). The taste receptor type 1 (TAS1R) family has three members that combine to sense sweet and umami tastes, and a distinct type 2 family (TAS2R) facilitates the perception of bitter tastes. Xu
et al
. determined the structures of the human bitter taste receptor TAS2R46 bound to a mini–G protein containing the TAS2R46-binding site from the G protein gustducin. The structures reveal distinct features of TAS2R46 compared with other GPCRs and provide insight into how ligands such as the bitter alkaloid strychnine activate this GPCR to evoke a bitter taste. —VV
A structure reveals insights into how a human bitter taste receptor recognizes a ligand and transduces the signal.
Liquid digestate with high concentration of organic matter and suspended solids cannot be directly used for microalgae cultivation. This study employed an innovative integrated approach, combining ...flocculation and biological contact oxidation (F-BCO), as a pretreatment to create a suitable environment for microalgae growth. The laboratory and pilot-scale experiments were both performed to verify operational performance. In F-BCO pretreatment, chemical oxygen demand (COD), NH3-N, and total phosphorus (TP) were reduced 55.0%, 46.1%, and 74.9%, respectively at pilot-scale in steady-state phase. It is further determined that the COD and TP removal were primarily attributed to flocculation, and NH3-N removal was mainly due to oxidation process (70%). The pretreated biogas slurry (BS) can be directly used for Chlorella cultivation, reaching a maximum accumulated biomass concentration of 3.3 g/L. The F-BCO process demonstrated a promising potential for pretreating BS to be a culture media for microalgae cultivation.
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•Flocculation-biological contact oxidation approach was applied to pretreat digestate.•Pilot-scale reactor removes 55% COD, 46% NH3-N and 75% TP, respectively.•The pretreated digestate can be directly used for Chlorella cultivation.•The maximum accumulated biomass can reach 3.3 g/L in 15 days.
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