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This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41586-020-2950-0 .
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The properties of graphene nanoribbons (GNRs)1-5-such as conductivity or semiconductivity, charge mobility and on/off ratio-depend greatly on their width, length and edge structure. Existing bottom-up methods used to synthesize GNRs cannot achieve control over all three of these parameters simultaneously, and length control is particularly challenging because of the nature of step-growth polymerization6-18. Here we describe a living annulative π-extension (APEX)19 polymerization technique that enables rapid and modular synthesis of GNRs, as well as control over their width, edge structure and length. In the presence of palladium/silver salts, o-chloranil and an initiator (phenanthrene or diphenylacetylene), the benzonaphthosilole monomer polymerizes in an annulative manner to furnish fjord-type GNRs. The length of these GNRs can be controlled by simply changing the initiator-to-monomer ratio, achieving the synthesis of GNR block copolymers. This method represents a type of direct C-H arylation polymerization20 and ladder polymerization21, activating two C-H bonds of polycyclic aromatic hydrocarbons and constructing one fused aromatic ring per chain propagation step.
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Kolbe dimerization and Hofer-Moest reactions are well-investigated carboxylic acid transformations, wherein new carbon-carbon and carbon-heteroatom bonds are constructed via electrochemical decarboxylation. These transformations can be switched by choosing an electrode that allows control of the reactive intermediate, such as carbon radical or carbocation. However, the requirement of a high current density diminishes the functional group compatibility with these electrochemical reactions. Here, we demonstrate the photocatalytic decarboxylative transformation of activated carboxylic acids in a switchable and functional group-compatible manner. We discovered that switching between Kolbe-type or Hofer-Moest-type reactions can be accomplished with suitable photocatalysts by controlling the reaction pathways: energy transfer (EnT) and single-electron transfer (SET). The EnT pathway promoted by an organo-photocatalyst yielded 1,2-diarylethane from arylacetic acids, whereas the ruthenium photoredox catalyst allows the construction of an ester scaffold with two arylmethyl moieties via the SET pathway. The resulting radical intermediates were coupled to olefins to realize multicomponent reactions. Consequently, four different products were selectively obtained from a simple carboxylic acid. This discovery offers new opportunities for selectively synthesizing multiple products via switchable reactions using identical substrates with minimal cost and effort.
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Optically active left (M)- and right (P)-handed helical syndiotactic poly(methyl methacrylate)s (M- and P-st-PMMAs) with a helicity memory enantioselectively encapsulated the racemic C60 derivatives, such as 3,4-fulleroproline tert-butyl ester (rac-1) and tetraallylated C60 (rac-2), as well as the C60-bound racemic 310-helical peptides (rac-3) within their helical cavities to form peapod-like inclusion complexes and a unique "helix-in-helix" superstructure, respectively. The enantiomeric excess (ee) and separation factor (enantioselectivity) (α) of the analyte 1 (ee = 23%-25% and α = 2.35-2.50) encapsulated within the helical cavities of the M- and P-st-PMMAs were higher than those of the analytes 2 and 3 (ee = 4.3%-6.0% and α = 1.28-1.50). The optically pure (S)- and (R)-1 were found to more efficiently induce an excess one-handed helical conformation in the st-PMMA backbone than the optically pure (S)- and (R)-1-phenylethylamine, resulting in intense mirror-image vibrational circular dichroism (VCD) spectra in the PMMA IR regions. The excess one-handed helices induced in the st-PMMAs complexed with (S)- and (R)-1 were memorized after replacement with the achiral C60, and the complexes exhibited induced electric CDs in the achiral C60 chromophore regions.
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The mature synthetic methodologies enable us to rationally design and produce chiral nanographenes (NGs), most of which consist of multiple helical motifs. However, inherent chirality originating from twisted geometry has just emerged to be employed in chiral NGs. Herein, we report a red-emissive chiral NG constituted of orthogonally arranged two-fold twisted π-skeletons at a contorted pyrene core which contributes to optical transitions of S0âS1 and vice versa. The thus-obtained NG exhibited a robustness on its redox properties through 2e- uptake/release. The chemical oxidation generated stable radical cation whose absorption covers near-infrared I and II regions. Overall, the contorted pyrene core governs electronic nature of the chiral NG. The twist operation on NGs would be, therefore, a design strategy to alter conventional chirality induction on NGs.
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Hole-transporting materials (HTMs) are essential for optoelectronic devices, such as organic light-emitting diodes (OLEDs), dye-sensitized solar cells, and perovskite solar cells. Triarylamines have been employed as HTMs since they were introduced in 1987. However, heteroatoms or side chains embedded in the core skeleton of triarylamines can cause thermal and chemical stability problems. Herein, we report that hexabenzo[a,c,fg,j,l,op]tetracene (HBT), a small nonplanar nanographene, functions as a hydrocarbon HTM with hole transport properties that match those of triarylamine-based HTMs. X-ray structural analysis and theoretical calculations revealed effective multidirectional orbital interactions and transfer integrals for HBT. In-depth experimental and theoretical analyses revealed that the nonplanarity-inducing annulative π-extension can achieve not only a stable amorphous state in bulk films, but also a higher increase in the highest occupied molecular orbital level than conventional linear or cyclic π-extension. Furthermore, an in-house manufactured HBT-based OLED exhibited excellent performance, featuring superior curves for current density-voltage, external quantum efficiency-luminance, and lifetime compared to those of representative triarylamine-based OLEDs. A notable improvement in device lifetime was observed for the HBT-based OLED, highlighting the advantages of the hydrocarbon HTM. This study demonstrates the immense potential of small nonplanar nanographenes for optoelectronic device applications.
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Peripheral structural modifications of arenes are widely used to control or improve the optoelectronic properties, molecular assembly, and stability of aromatic π-materials as well as to explore new functions. However, known modifications are often tedious and complex; therefore, a simple yet powerful modification strategy is needed. We discovered that annulation with a simple adamantane scaffold exerts a significant impact on the properties, alignment, and stability of aromatic π-systems. This unprecedented adamantane annulation was achieved by a two-step transformation of metallated arenes and 4-protoadamantanone, generating a range of adamantane-annulated arenes. Analysis of structural and electronic properties uncovered unique effects of the process, such as high solubility and enhanced conjugation. The oxidation of adamantane-annulated perylenes produced strikingly stable cationic species with emission extended to the near-infrared region. This simple property modulation of aromatic π-systems would not only create potentially ground-breaking π-materials but also novel nanocarbon materials, such as diamond-graphene hybrids.
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Among a large variety of organic semiconducting materials, rubrene (5,6,11,12-tetraphenyltetracene) represents one of the most prominent molecular entities mainly because of its unusually high carrier mobility. Toward finding superior rubrene-based organic semiconductors, several synthetic strategies for related molecules have been established. However, despite its outstanding properties and significant attention in the field of materials science, late-stage functionalizations of rubrene remains undeveloped, thereby limiting the accessible chemical space of rubrene-based materials. Herein, we report on a late-stage π-extension of rubrene by dearomative annulative π-extension (DAPEX), leading to the generation of rubrene derivatives having an extended acene core. The Diels-Alder reaction of rubrene with 4-methyl-1,2,4-triazoline-3,5-dione occurred to give 1:1 and 1:2 cycloadducts which further underwent iron-catalyzed annulative diarylation. The thus-formed 1:1 and 1:2 adducts were subjected to radical-mediated oxidation and thermal cycloreversion to furnish one-side and two-side π-extended rubrenes, respectively. These π-extended rubrenes displayed a marked red shift in absorption and emission spectra, clearly showing that the acene π-system of rubrene was extended not only structurally but also electronically. The X-ray crystallographic analysis uncovered interesting packing modes of these π-extended rubrenes. Particularly, two-side π-extended rubrene adopts a brick-wall packing structure with largely overlapping two-dimensional face-to-face π-π interactions. Finally, organic field-effect transistor devices using two-side π-extended rubrene were fabricated, and their carrier mobilities were measured. The observed maximum hole mobility of 1.49 × 10-3 cm2V-1 s-1, which is a comparable value to that of the thin-film transistor using rubrene, clearly shows the potential utility of two-side π-extended rubrene in organic electronics.
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Expanded carbohelicenes with structures fused to 15- and 17-benzene were successfully synthesized. Establishing a new synthetic strategy is crucial to realize the development of longer expanded [2,1][n]helicenes with a kekulene-like projection drawing structure. This article describes the sequential integration of the π-elongating Wittig reaction of functionalized phenanthrene units and ring-fusing Yamamoto coupling for the synthesis of [2,1][15]helicenes and [2,1][17]helicenes. X-ray crystallographic structures, photophysical properties, and density functional theory (DFT) calculations revealed the unique characteristics of the synthesized expanded helicenes. Furthermore, because of the high enantiomerization barrier derived from a wide-range intrahelix π-π interaction, the optical resolution of [2,1][17]helicene was successfully achieved, and chiroptical properties such as circular dichroism and circularly polarized luminescence were elucidated for the first time as enantiomers of pristine [2,1][n]helicene core.
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Cycloparaphenylenes (CPPs) and carbon nanobelts (CNBs) represent some of the most iconic cyclic molecular nanocarbons in recent chemistry owing to their unique properties derived from rigid, strained, and cyclic π-conjugated systems. In the last decade, the synthesis of various sizes of CPPs and CNBs has been achieved that allowed not only for investigating their size-dependent properties and strategically using such properties in various applications but also understanding the fundamental features of cyclic π-conjugated systems and molecular nanocarbons in general. Herein, we report on the synthesis, size-dependent properties, and paratropic belt currents of methylene-bridged [n]cycloparaphenylenes ([n]MCPP, n = 6, 8, 10). [8]MCPP and [10]MCPP were synthesized by the same strategy we developed for [6]MCPP synthesis. With readily available ethoxy-substituted pillar[8]arene and pillar[10]arene as precursors, [8]MCPP and [10]MCPP were successfully synthesized in three steps consisting of de-ethylation, triflation, and nickel-mediated aryl-aryl coupling. The structural and electronic properties of MCPPs were investigated by nuclear magnetic resonance analyses, absorption/fluorescence measurements, X-ray crystallographic analyses, and computational studies, revealing their interesting size-dependent properties. The differences in the size dependency between MCPPs and CPPs reflect the belt-form features of MCPPs, namely, methylene-bridging effects on MCPPs. Moreover, an interesting paratropic belt current along the MCPP backbone has been uncovered both experimentally and theoretically. The 1H NMR chemical shifts of MCPPs confirmed the presence of a paratropic belt current, whose strength rapidly decreases with increasing nanobelt size.
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Cyclodehydrogenation is an essential synthetic method for the preparation of polycyclic aromatic hydrocarbons, polycyclic heteroaromatic compounds, and nanographenes. Among the many examples, anionic cyclodehydrogenation using potassium(0) has attracted synthetic chemists because of its irreplaceable reactivity and utility in obtaining rylene structures from binaphthyl derivatives. However, existing methods are difficult to use in terms of practicality, pyrophoricity, and lack of scalability and applicability. Herein, we report the development of a lithium(0)-mediated mechanochemical anionic cyclodehydrogenation reaction for the first time. This reaction could be easily performed using a conventional and easy-to-handle lithium(0) wire at room temperature, even under air, and the reaction of 1,1'-binaphthyl is complete within 30 min to afford perylene in 94% yield. Using this novel and user-friendly protocol, we investigated substrate scope, reaction mechanism, and gram-scale synthesis. As a result, remarkable applicability and practicality over previous methods, as well as limitations, were comprehensively studied by computational studies and nuclear magnetic resonance analysis. Furthermore, we demonstrated two-, three-, and five-fold cyclodehydrogenations for the synthesis of novel nanographenes. In particular, quinterrylene ([5]rylene or pentarylene), the longest nonsubstituted molecular rylene, was synthesized for the first time.
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Circadian clocks are biological timekeeping systems that coordinate genetic, metabolic and physiological behaviors with the external day-night cycle. The clock in plants relies on the transcriptional-translational feedback loops transcription-translation feedback loop (TTFL), consisting of transcription factors including PSUEDO-RESPONSE REGULATOR (PRR) proteins, plant lineage-specific transcriptional repressors. Here, we report that a novel synthetic small-molecule modulator, 5-(3,4-dichlorophenyl)-1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4,6(5H)-dione (TU-892), affects the PRR7 protein amount. A clock reporter line of Arabidopsis was screened against the 10,000 small molecules in the Maybridge Hitfinder 10K chemical library. This screening identified TU-892 as a period-lengthening molecule. Gene expression analyses showed that TU-892 treatment upregulates CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) mRNA expression. TU-892 treatment reduced the amount of PRR7 protein, a transcriptional repressor of CCA1. Other PRR proteins including TIMING OF CAB EXPRESSION 1 were altered less by TU-892 treatment. TU-892-dependent CCA1 upregulation was attenuated in mutants impaired in PRR7. Collectively, TU-892 is a novel type of clock modulator that reduces the levels of PRR7 protein.
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Proteínas de Arabidopsis , Arabidopsis , Relojes Circadianos , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ritmo Circadiano/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Arabidopsis/metabolismo , Relojes Circadianos/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
Plant seedlings adjust the growth of the hypocotyl in response to surrounding environmental changes. Genetic studies have revealed key players and pathways in hypocotyl growth, such as phytohormones and light signaling. However, because of genetic redundancy in the genome, it is expected that not-yet-revealed mechanisms can be elucidated through approaches different from genetic ones. Here, we identified a small compound, HYGIC (HG), that simultaneously induces hypocotyl elongation and thickening, accompanied by increased nuclear size and enlargement of cortex cells. HG-induced hypocotyl growth required the ethylene signaling pathway activated by endogenous ethylene, involving CONSTITUTIVE PHOTOMORPHOGENIC 1, ETHYLENE INSENSITIVE 2 (EIN2) and redundant transcription factors for ethylene responses, ETHYLENE INSENSITIVE 3 (EIN3) and EIN3 LIKE 1. By using EBS:GUS, a transcriptional reporter of ethylene responses based on an EIN3-binding-cis-element, we found that HG treatment ectopically activates ethylene responses at the epidermis and cortex of the hypocotyl. RNA-seq and subsequent gene ontology analysis revealed that a significant number of HG-induced genes are related to responses to hypoxia. Indeed, submergence, a representative environment where the hypoxia response is induced in nature, promoted ethylene-signaling-dependent hypocotyl elongation and thickening accompanied by ethylene responses at the epidermis and cortex, which resembled the HG treatment. Collectively, the identification and analysis of HG revealed that ectopic responsiveness to ethylene promotes hypocotyl growth, and this mechanism is activated under submergence.
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Proteínas de Arabidopsis , Arabidopsis , Hipocótilo/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Transducción de Señal/fisiología , Etilenos/farmacología , Etilenos/metabolismo , Hipoxia , Regulación de la Expresión Génica de las PlantasRESUMEN
Positron emission tomography (PET) is a powerful imaging tool that enables early in vivo detection of Alzheimer's disease (AD). For this purpose, various PET ligands have been developed to image ß-amyloid and tau protein aggregates characteristically found in the brain of AD patients. In this study, we initiated to develop another type of PET ligand that targets protein kinase CK2 (formerly termed as casein kinase II), because its expression level is known to be altered in postmortem AD brains. CK2 is a serine/threonine protein kinase, an important component of cellular signaling pathways that control cellular degeneration. In AD, the CK2 level in the brain is thought to be elevated by its involvement in both phosphorylation of proteins such as tau and neuroinflammation. Decreased CK2 activity and expression levels lead to ß-amyloid accumulation. In addition, since CK2 also contributes to the phosphorylation of tau protein, the expression level and activity of CK2 is expected to undergo significant changes during the progression of AD pathology. Furthermore, CK2 could act as a potential target for modulating the inflammatory response in AD. Therefore, PET imaging targeting CK2 expressed in the brain could be a useful another imaging biomarker for AD. We synthesized and radiolabeled a CK2 inhibitor, [11C]GO289, in high yields from its precursor and [11C]methyl iodide under basic conditions. On autoradiography, [11C]GO289 specifically bound to CK2 in both rat and human brain sections. On baseline PET imaging, this ligand entered and rapidly washed out of the rat brain with its peak activity rather being small (SUV < 1.0). However, on blocking, there was no detectable CK2 specific binding signal. Thus, [11C]GO289 may be useful in vitro but not so in vivo in its current formulation. The lack of detectable specific binding signal in the latter may be due to a relatively high component of nonspecific binding signal in the overall rather weak PET signal, or it may also be related to the known fact that ATP can competitively binds to subunits of CK2, reducing its availability for this ligand. In the future, it will be necessary for PET imaging of CK2 to try out different non-ATP competitive formulations of CK2 inhibitor that can also provide significantly higher in vivo brain penetration.
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Enfermedad de Alzheimer , Quinasa de la Caseína II , Humanos , Ratas , Animales , Ligandos , Tomografía de Emisión de Positrones/métodos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
Single-walled carbon nanotubes (SWCNT) have long attracted attention due to their distinct physical properties, depending on their chiral structures (chiralities). Clarifying their growth mechanism is important toward perfect chirality-controlled bulk synthesis. Although a correlation between the chirality distribution and the carbon atom configuration at an open tube edge has been predicted theoretically, lack of sufficient statistical data on metallic and semiconducting SWCNTs prohibited its verification. Here, we report statistical verification of the chirality distribution of 413 as-grown individual air-suspended SWCNTs with a length of over 20 µm using broadband Rayleigh spectroscopy. After excluding the impact of the difference in the number of possible SWCNT structures per chiral angle interval, the abundance profile with chiral angle exhibits an increasing trend with a distinct anomaly at a chiral angle of approximately 20°. These results are well explained considering the growth rate depending on armchair-shaped site configurations at the catalyst-nanotube interface.
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Nanocarbons incorporating non-hexagonal aromatic rings - such as five-, seven-, and eight-membered rings - have various intriguing physical properties such as curved structures, unique one-dimensional packing, and promising magnetic, optical, and conductivity properties. Herein, we report an efficient synthetic approach to polycyclic aromatics containing seven-membered rings via a palladium-catalyzed intramolecular Ar-H/Ar-Br coupling. In addition to all-hydrocarbon scaffolds, heteroatom-embedded heptagon-containing polyarenes can be efficiently constructed with this method. Rhodium- and palladium-catalyzed sequential six- and seven-membered ring formations also afford complex heptagon-containing molecular nanocarbons from readily available arylacetylenes and biphenyl boronic acids. Detailed mechanistic analysis by DFT calculations showed the feasibility of seven-membered ring formation by a concerted metalation-deprotonation mechanism. This reaction can serve as a template for the synthesis of a wide range of seven-membered ring-containing molecular nanocarbons.
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The active metal template (AMT) strategy is a powerful tool for the formation of mechanically interlocked molecules (MIMs) such as rotaxanes and catenanes, allowing the synthesis of a variety of MIMs, including π-conjugated and multicomponent macrocycles. Cycloparaphenylene (CPP) is an emerging molecule characterized by its cyclic π-conjugated structure and unique properties. Therefore, diverse modifications of CPPs are necessary for its wide application. However, most CPP modifications require early stage functionalization and the direct modification of CPPs is very limited. Herein, we report the synthesis of a catenane consisting of [9]CPP and a 2,2'-bipyridine macrocycle as a new CPP analogue that contains a reliable synthetic scaffold enabling diverse and concise post-modification. Following the AMT strategy, the [9]CPP-bipyridine catenane was successfully synthesized through Ni-mediated aryl-aryl coupling. Catalytic C-H borylation/cross-coupling and metal complexation of the bipyridine macrocycle moiety, an effective post-functionalization method, were also demonstrated with the [9]CPP-bipyridine catenane. Single-crystal X-ray structural analysis revealed that the [9]CPP-bipyridine catenane forms a tridentated complex with an Ag ion inside the CPP ring. This interaction significantly enhances the phosphorescence lifetime through improved intermolecular interactions.
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New forms of molecular nanocarbon particularly looped polyarenes adopting various topologies contribute to the fundamental science and practical applications. Here we report the synthesis of an infinity-shaped polyarene, infinitene (1) (cyclo[c.c.c.c.c.c.e.e.e.e.e.e]dodecakisbenzene), comprising consecutively fused 12-benzene rings forming an enclosed loop with a strain energy of 60.2 kcal·mol-1. Infinitene (1) represents a topoisomer of still-hypothetical [12]circulene, and its scaffold can be formally visualized as the outcome of the "stitching" of two homochiral [6]helicene subunits by both their ends. The synthetic strategy encompasses transformation of a rationally designed dithiacyclophane to cyclophadiene through the Stevens rearrangement and pyrolysis of the corresponding S,S'-bis(oxide) followed by the photocyclization. The structure of 1 is a unique hybrid of helicene and circulene with a molecular formula of C48H24, which can be regarded as an isomer for kekulene, [6,6]carbon nanobelt ([6,6]CNB), and [12]cyclacene. Infinitene (1) is a bench-stable yellow solid with green fluorescence and soluble to common organic solvents. Its figure-eight molecular structure was unambiguously confirmed by X-ray crystallography. The scaffold of 1 is significantly compressed as manifested by a remarkably shortened distance (3.152-3.192 Å) between the centroids of two π-π stacked central benzene rings and the closest C···C distance of 2.920 Å. Fundamental photophysical properties of 1 were thoroughly elucidated by UV-vis absorption and fluorescence spectroscopic studies and density functional theory calculations. Its configurational stability enabled separation of the corresponding enantiomers (P,P) and (M,M) by a chiral HPLC. Circular dichroism (CD) and circularly polarized luminescence (CPL) measurements revealed that 1 has moderate |gCD| and |gCPL| values.
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The circadian clock is an internal timekeeping system that governs about 24 h biological rhythms of a broad range of developmental and metabolic activities. The clocks in eukaryotes are thought to rely on lineage-specific transcriptional-translational feedback loops. However, the mechanisms underlying the basic transcriptional regulation events for clock function have not yet been fully explored. Here, through a combination of chemical biology and genetic approaches, we demonstrate that phosphorylation of RNA polymerase II by CYCLIN DEPENDENT KINASE C; 2 (CDKC;2) is required for maintaining the circadian period in Arabidopsis. Chemical screening identified BML-259, the inhibitor of mammalian CDK2/CDK5, as a compound lengthening the circadian period of Arabidopsis. Short-term BML-259 treatment resulted in decreased expression of most clock-associated genes. Development of a chemical probe followed by affinity proteomics revealed that BML-259 binds to CDKC;2. Loss-of-function mutations of cdkc;2 caused a long period phenotype. In vitro experiments demonstrated that the CDKC;2 immunocomplex phosphorylates the C-terminal domain of RNA polymerase II, and BML-259 inhibits this phosphorylation. Collectively, this study suggests that transcriptional activity maintained by CDKC;2 is required for proper period length, which is an essential feature of the circadian clock in Arabidopsis.
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Proteínas de Arabidopsis , Arabidopsis , Relojes Circadianos , Animales , Arabidopsis/fisiología , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Regulación de la Expresión Génica de las Plantas , Mamíferos/metabolismo , Fosforilación , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismoRESUMEN
CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY-compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure.