Recently developed CsPbX3 (X = Cl, Br, and I) perovskite quantum dots (QDs) hold great potential for various applications owing to their superior optical properties, such as tunable emissions, high ...quantum efficiency, and narrow linewidths. However, poor stability under ambient conditions and spontaneous ion exchange among QDs hinder their application, for example, as phosphors in white‐light‐emitting diodes (WLEDs). Here, a facile two‐step synthesis procedure is reported for luminescent and color‐tunable CsPbX3–zeolite‐Y composite phosphors, where perovskite QDs are encapsulated in the porous zeolite matrix. First zeolite‐Y is infused with Cs+ ions by ion exchange from an aqueous solution and then forms CsPbX3 QDs by diffusion and reaction with an organic solution of PbX2. The zeolite encapsulation reduces degradation and improves the stability of the QDs under strong illumination. A WLED is fabricated using the resulting microscale composites, with Commission Internationale de I'Eclairage (CIE) color coordinates (0.38, 0.37) and achieving 114% of National Television Standards Committee (NTSC) and 85% of the ITU‐R Recommendation BT.2020 (Rec.2020) coverage.
A synthesis procedure for luminescent perovskite quantum dots embedded in zeolite‐Y crystals is presented. The structural and optical properties of the resulting composites are characterized in detail. Zeolite embedding improves the stability of perovskite quantum dots to degradation. Finally, the composites are used to produce a white‐light‐emitting diode with wide color gamut.
Dopamine receptors are implicated in the pathogenesis and treatment of nearly every neuropsychiatric disorder. Although thousands of drugs interact with these receptors, our molecular understanding ...of dopaminergic drug selectivity and design remains clouded. To illuminate dopamine receptor structure, function, and ligand recognition, we determined crystal structures of the D₄ dopamine receptor in its inactive state bound to the antipsychotic drug nemonapride, with resolutions up to 1.95 angstroms. These structures suggest a mechanism for the control of constitutive signaling, and their unusually high resolution enabled a structure-based campaign for new agonists of the D₄ dopamine receptor. The ability to efficiently exploit structure for specific probe discovery—rapidly moving from elucidating receptor structure to discovering previously unrecognized, selective agonists—testifies to the power of structure-based approaches.
The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It ...is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 Å resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The peptide hormone angiotensin II regulates blood pressure mainly through the type 1 angiotensin II receptor AT1R and its downstream signaling proteins Gq and β‐arrestin. AT1R blockers, clinically ...used as antihypertensive drugs, inhibit both signaling pathways, whereas AT1R β‐arrestin‐biased agonists have shown great potential for the treatment of acute heart failure. Here, we present a cryo‐electron microscopy (cryo‐EM) structure of the human AT1R in complex with a balanced agonist, Sar1‐AngII, and Gq protein at 2.9 Å resolution. This structure, together with extensive functional assays and computational modeling, reveals the molecular mechanisms for AT1R signaling modulation and suggests that a major hydrogen bond network (MHN) inside the receptor serves as a key regulator of AT1R signal transduction from the ligand‐binding pocket to both Gq and β‐arrestin pathways. Specifically, we found that the MHN mutations N1113.35A and N2947.45A induce biased signaling to Gq and β‐arrestin, respectively. These insights should facilitate AT1R structure‐based drug discovery for the treatment of cardiovascular diseases.
Synopsis
Angiotensin (Ang) II hormone binding to AT1R receptors activates both Gq and β‐arrestin signaling to elevate blood pressure and confer heart protection, respectively. The AT1R‐Gq‐Sar1‐AngII structure combined with functional and computational studies reveals that the crucial role of a major hydrogen bond network in biasing AT1R in either direction.
A Cryo‐EM structure depicts human angiotensin II type I receptor (AT1R) activated by the balanced agonist Sar1‐AngII and coupled to its canonical transducer Gq at 2.9 Å resolution.
A combination of BRET assays and molecular dynamic simulations defines the structural characteristics of Gq‐biased agonists TRV055/TRV056.
A major hydrogen bond network (MHN) in the core of AT1R is crucial for AT1R signaling modulation.
The cryo‐EM structure of the AT1R‐Gq‐Sar1‐AngII complex combined with extensive functional assays and molecular dynamic simulations shows that a major hydrogen bond network determines signaling toward Gq vs. β‐arrestin.
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT
and MT
. Circadian release of melatonin at ...night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle
. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep
and depression
. Despite their importance, few in vivo active MT
-selective ligands have been reported
, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT
crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT
inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT
-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT
- but not in MT
-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT
-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
Drugs active at G protein–coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased ...signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT 2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT 1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT 2B receptor bound to ERG and compared it with the 5-HT 1B /ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.
The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3-5 and other areas of biology6,7. Here we determined the crystal structure of this receptor ...in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3-5 and other areas of biology6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.
The dopamine system, including five dopamine receptors (D1R–D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many ...neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson’s disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for Gi protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.
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•Structures of dopamine receptor D3R with agonists pramipexole and PD128907•Different binding modes of agonists with similar pharmacological properties to D3R•Conformational changes associated with D3R activation and selective G protein coupling•Selective mechanism of agonists to D3R versus D2R and D4R
Xu et al. report two cryo-EM structures of dopamine receptor D3R bound to Gi protein and D3R-selective agonists, PD128907 and the Parkinson’s disease drug pramipexole. The structures reveal the basis of ligand selectivity, ligand-induced D3R activation, and selective Gi coupling by D3R.
The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has ...been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics.
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•κ-opioid receptor active-state crystal structure disclosed•κ-opioid receptor structure reveals features involved in biased signaling•Structure provides template for the creation of safe and effective analgesics
A crystal structure of the active κ-opioid receptor provides a guide for the development of safe and effective new analgesics.
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