ABSTRACT
The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants1-3. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction.
Subject(s)
Benztropine , Dopamine Plasma Membrane Transport Proteins , Dopamine Uptake Inhibitors , Dopamine , Humans , Apoproteins/metabolism , Apoproteins/chemistry , Attention Deficit Disorder with Hyperactivity/drug therapy , Benztropine/metabolism , Benztropine/pharmacology , Binding Sites , Cocaine/pharmacology , Cocaine/metabolism , Cocaine-Related Disorders/drug therapy , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/antagonists & inhibitors , Dopamine Plasma Membrane Transport Proteins/chemistry , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/metabolism , Dopamine Uptake Inhibitors/pharmacology , Methylphenidate/metabolism , Methylphenidate/pharmacology , Models, Molecular , Piperazines/metabolism , Piperazines/pharmacology , Protein Binding , Protein ConformationABSTRACT
The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons1-3. It is a pharmacological target for various antidepressants and analgesic drugs4,5. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlAEM), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na+ and Cl- undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlAEM provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design.
Subject(s)
Bupropion , Models, Molecular , Norepinephrine Plasma Membrane Transport Proteins , Norepinephrine , Piperazines , Humans , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Norepinephrine Plasma Membrane Transport Proteins/chemistry , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Norepinephrine/metabolism , Bupropion/metabolism , Bupropion/chemistry , Bupropion/pharmacology , Piperazines/pharmacology , Piperazines/chemistry , Piperazines/metabolism , Allosteric Regulation/drug effects , Binding Sites , Biological Transport , Sodium/metabolism , Protein Conformation , Protein Binding , ThiazolesABSTRACT
A metasurface array for electromagnetic (EM) energy harvesting for Wi-Fi bands is presented in this paper; the metasurface array consists of a metasurface unit, a rectifier, and a load resistor. Each row of unit cells in the array is interconnected to form an energy transfer channel, which enables the transfer and concentration of incident power. Furthermore, at the terminal of the channel, a single series diode rectifier circuit and a load resistor are integrated in a coplanar manner. It is used to rectify the energy in Wi-Fi bands and enables DC energy harvesting across the load. Finally, a 5 × 7 prototype of the metasurface array is fabricated and measured for the verification of the rationality of the design. Testing in an anechoic chamber shows that the prototype achieves a 72% RF-DC efficiency at 5.9 GHz when the available incident power is about 7 dBm.
ABSTRACT
The synthesis of the accurate composition and morphological/structural design of multielement semiconductor materials is considered an effective strategy for obtaining high-performance hybrid photocatalysts. Herein, sulfur vacancy (Vs)-bearing In2S3/CuInS2 microflower heterojunctions (denoted Vs-In2S3/CuInS2) were formed in situ using In2S3 microsphere template-directed synthesis and a metal ion exchange-mediated growth strategy. Photocatalysts with flower-like microspheres can be obtained using hydrothermally synthesized In2S3 microspheres as a template, followed by Ostwald ripening growth during the metal cation exchange of Cu+ and In3+. The optimal heterostructured Vs-In2S3/CuInS2 microflowers exhibited CO and CH4 evolution rates of 80.3 and 11.8 µmol g-1 h-1, respectively, under visible-light irradiation; these values are approximately 4 and 6.8 times higher than those reported for pristine In2S3, respectively. The enhanced photocatalytic performance of the Vs-In2S3/CuInS2 catalysts could be attributed to the synergistic effects of the following factors: (i) the constructed heterojunctions accelerate charge-carrier separation; (ii) the flower-like microspheres exhibit highly uniform morphologies and compositions, which enhance electron transport and light harvesting; and (iii) the vs. may trap excited electrons and, thus, inhibit charge-carrier recombination. This study not only confirms the feasibility of the design of heterostructures on demand, but also presents a simple and efficient strategy to engineer metal sulfide photocatalysts with enhanced photocatalytic performance.
ABSTRACT
The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.
Subject(s)
Glycine Plasma Membrane Transport Proteins , Humans , Biological Transport , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins/chemistry , Glycine Plasma Membrane Transport Proteins/metabolism , Glycine Plasma Membrane Transport Proteins/ultrastructure , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/metabolism , Synaptic Transmission , Imidazoles/chemistry , Sarcosine/analogs & derivatives , Piperidines/chemistryABSTRACT
The voltage-gated calcium channel CaV1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of CaV1.2 are involved in brain and heart diseases. Pharmacological inhibition of CaV1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of CaV1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6II, S6III, and S6IV helices and forms extensive hydrophobic interactions with CaV1.2. Our structure elucidates that benidipine is located in the DIII-DIV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5DIII, S6DIII, and S6DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.
Subject(s)
Calcium Channels, L-Type , Calcium Channels, L-Type/metabolism , Protein Structure, SecondaryABSTRACT
Transition metal sulfides have become more and more important in the field of energy storage due to their superior chemical and physical properties. Herein, dahlia ß-NiS with a rough surface and ß-NiS@reduced graphene oxide (rGO) have been green synthesized by a one-step hydrothermal method. The interface characteristics of ß-NiS@ rGO composites have been systematically studied by XPS, Raman, and first-principles calculations. It is found that the residual O atoms in the interface and the polarization charge generated by them play an important role in performance enhancement. The NiS@rGO composite material has the best electrochemical performance when the C/O ratio is 6.48. Furthermore, we designed a NiS@rGO//rGO asymmetric supercapacitor with a potential window of 1.7 V. Its excellent energy density and power density demonstrate the advantages of the optimized NiS@rGO electrode. When the power density is 850 W kg-1, the energy density can reach 40.4 W h kg-1. Even at a power density of up to 6800 W kg-1, the energy density can be maintained at 17.6 W h kg-1. These encouraging results provide a possible pathway for designing asymmetric supercapacitors with ultra-high performance and a feasible strategy for the precise control of electrochemical performance.
ABSTRACT
High-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and ß1 subunits. The VSDII is stabilized in the resting state. Electrophysiological experiments elucidate that the VSDII is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.
Subject(s)
Calcium Channels, R-Type , Cation Transport Proteins , Humans , Cryoelectron Microscopy , Calcium Channels, R-Type/physiology , Cation Transport Proteins/physiologyABSTRACT
A dual-band metasurface array is presented in this paper for electromagnetic (EM) energy harvesting in the Wi-Fi band and Ku band. The array consists of metasurface unit cells, rectifiers, and load resistors. The metasurface units within each column are interconnected to establish two channels of energy delivery, enabling the transmission and aggregation of incident power. At the terminals of two channels, a single series diode rectifier and a voltage doubler rectifier are integrated into them to rectify the energy in the Wi-Fi band and the Ku band, respectively. A 7 × 7 prototype of the metasurface array is fabricated and tested. The measured results in the anechoic chamber show that the RF-to-dc efficiencies of the prototype at 2.4 GHz and 12.6 GHz reach 64% and 55% accordingly, when the available incident power at the surface is 3 dBm and 14 dBm, respectively.
ABSTRACT
As a highly conserved endocytic mechanism during evolution, macropinocytosis is enhanced in several malignant tumors, which promotes tumor growth by ingesting extracellular nutrients. Recent research has emphasized the crucial role of macropinocytosis in tumor immunity. In the present study, we established a new macropinocytosis-related algorithm comprising molecular subtypes and a prognostic signature, in which patients with lung adenocarcinoma (LUAD) were classified into different clusters and risk groups based on the expression of 16 macropinocytosis-related long noncoding RNAs. According to the molecular subtypes, we discovered that patients with LUAD in cluster1 had a higher content of stromal cells and immune cells, stronger intensity of immune activities, higher expression of PD1, PDL1, and HAVCR2, and a higher tumor mutational burden, while patients in cluster2 exhibited better survival advantages. Furthermore, the constructed prognostic signature revealed that low-risk patients showed better survival outcomes, earlier tumor stage, higher abundance of stromal cells and immune cells, higher immune activities, higher expression of PD1, PDL1, CTLA4, and HAVCR2, and more sensitivity to Paclitaxel and Erlotinib. By contrast, patients with high scores were more suitable for Gefitinib treatment. In conclusion, the novel algorithm that divided patients with LUAD into different groups according to their clusters and risk groups, which could provide theoretical support for predicting their survival outcomes and selecting drugs for chemotherapy, targeted therapy, and immunotherapy.
Subject(s)
Adenocarcinoma of Lung , Antineoplastic Agents , Lung Neoplasms , RNA, Long Noncoding , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Algorithms , Antineoplastic Agents/therapeutic use , CTLA-4 Antigen , Computational Biology , Erlotinib Hydrochloride , Gefitinib , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Paclitaxel , Prognosis , RNA, Long Noncoding/geneticsABSTRACT
Multiple-band degeneracy has been widely recognized to be beneficial for high thermoelectric performance. Here, we discover that the p-type Dirac bands with lower degeneracy synergistically produce a higher Seebeck coefficient and electrical conductivity in topological semimetal BaAgBi. The anomalous transport phenomenon intrinsically originated from the asymmetric electronic structures: (i) complete p-type Dirac bands near the Fermi level facilitate high and strong energy-dependent hole relaxation time; (ii) the presence of additional parabolic conduction valleys allows for a large density of states to accept scattered electrons, leading to an enlarged hole-electron relaxation time ratio and, thus, weakened bipolar effect. In combination with the strong lattice anharmonicity, an exceptional p-type average ZT of 0.42 is achieved from 300 to 600 K, which can be dramatically enhanced to 1.38 via breaking the C3v symmetry. This work uncovers the underlying mechanisms governing the abnormal transport behavior in Dirac semimetal BaAgBi and highlights the asymmetric electronic structures as target features to discover/design high-performance thermoelectric materials.
ABSTRACT
Ni3S4 is regarded as one of the promising electrode materials for energy storage, but the difficulty in obtaining its pure phase hinders its wide applications. In this work, we introduced a novel method to in-situ synthesize Ni3S4@reduced graphene oxide (rGO) composite, where graphene oxide (GO) was found to induce the oxidation of Ni2+ to Ni3+ and the morphology transformation from microbar to polyhedron during the hydrothermal process. The influence of the content and oxidation degree of GO on the phase composition and morphology of nickel sulfide is investigated. It is found that the oxygen-containing functional group of GO is responsible for the change of valence state, which thus drives the transformation of NiS/Ni3S4 towards Ni3S4. The obtained Ni3S4@rGO composite shows a high energy storage capacity (1830 F g-1 at 2 A g-1), remarkably higher than the unpurified phase NiS/Ni3S4 (830 F g-1). Correspondingly, the assembled asymmetry supercapacitor indicates a high energy density of 37.3 Wh kg-1 at a power density of 398â¯Wâ¯kg-1. More importantly, the capacitance retention reaches 91.4 % after 10,000 cycles at a current density of 2 A g-1. Thus, this research overcomes the difficulty of synthesizing the pure Ni3S4 phase, which provides a new available pathway for constructing high-performance electrode materials.
ABSTRACT
TADB2.0 (http://bioinfo-mml.sjtu.edu.cn/TADB2/) is an updated database that provides comprehensive information about bacterial type II toxin-antitoxin (TA) loci. Compared with the previous version, the database refined and the new data schema is employed. With the aid of text mining and manual curation, it recorded 6193 type II TA loci in 870 replicons of bacteria and archaea, including 105 experimentally validated TA loci. In addition, the newly developed tool TAfinder combines the homolog searches and the operon structure detection, allowing the prediction for type II TA pairs in bacterial genome sequences. It also helps to investigate the genomic context of predicted TA loci for putative virulence factors, antimicrobial resistance determinants and mobile genetic elements via alignments to the specific public databases. Additionally, the module TAfinder-Compare allows comparing the presence of the given TA loci across the close relative genomes. With the recent updates, TADB2.0 might provide better support for understanding the important roles of type II TA systems in the prokaryotic life activities.
Subject(s)
Bacterial Toxins/genetics , Databases, Genetic , Genes, Bacterial , RNA, Bacterial/genetics , RNA, Small Untranslated/genetics , Bacteria/genetics , Bacterial Physiological Phenomena , Bacterial Toxins/antagonists & inhibitors , Bacterial Toxins/classification , Chromosomes, Bacterial/genetics , Data Mining , Datasets as Topic , Genome, Bacterial , Operon/genetics , Plasmids/genetics , Prophages/genetics , Species SpecificityABSTRACT
Klebsiella pneumoniae is an increasingly important bacterial pathogen to human. This Gram-negative bacterium species has become a serious concern due to its dramatic increase in the levels of multiple antibiotic resistances, particularly to carbapenems. The toxin-antitoxin (TA) system has recently been reported to be involved in the formation of drug-tolerant persister cells. The type II TA system is composed of a stable toxin protein and a relatively unstable antitoxin protein that is able to inhibit the toxin. Here, we examine the type II TA locus distribution and compare the TA diversity throughout ten completely sequenced K. pneumoniae genomes by using bioinformatics approaches. Two hundred and twelve putative type II TA loci were identified in 30 replicons of these K. pneumoniae strains. The amino acid sequence similarity-based grouping shows that these loci distribute differently not only among different K. pneumoniae strains isolated from diverse sources, but also between their chromosomes and plasmids.
Subject(s)
Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Genome, Bacterial/genetics , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/metabolism , Antitoxins/genetics , Antitoxins/metabolism , Bacterial Toxins/genetics , Bacterial Toxins/metabolism , Chromosomes, Bacterial/genetics , Plasmids/geneticsABSTRACT
Artificial nest can improve the breeding success of birds in the field, and it has been proved to be more effective to endangered species. We surveyed the structure characteristics of natural nest and the status of the use of artificial nests for oriental white stork, Ciconia boyciana, in Honghe National Nature Reserve, Heilongjiang Province. Differences were investigated among the structure characteristics of the used and unused artificial nests, and natural nests based on one-way ANOVA. It was observed that significant differences in the diameter of nest branch, the vertical an- gle between nest branch, the height of the jointthe height of the nest above ground exited in different nest types. On account of the structure characteristics of the natural nests of C. boyciana, the suitable diameter of nest pillar for artificial nest frame should be 15.0-25.0 cm with the height of 5.0-12.0 m, which would be better if they were constructed by some acid-resistant materials, e.g., cement. The number of nest stands should be 3-4 individuals with the diameter of 9.0-12.0 cm, the vertical angle of 45 degrees-60 degrees, and the length of 90.0-140.0 cm.
Subject(s)
Birds , Breeding , Conservation of Natural Resources , Analysis of Variance , Animals , Nesting BehaviorABSTRACT
ICEberg (http://db-mml.sjtu.edu.cn/ICEberg/) is an integrated database that provides comprehensive information about integrative and conjugative elements (ICEs) found in bacteria. ICEs are conjugative self-transmissible elements that can integrate into and excise from a host chromosome. An ICE contains three typical modules, integration and excision, conjugation, and regulation modules, that collectively promote vertical inheritance and periodic lateral gene flow. Many ICEs carry likely virulence determinants, antibiotic-resistant factors and/or genes coding for other beneficial traits. ICEberg offers a unique, highly organized, readily explorable archive of both predicted and experimentally supported ICE-relevant data. It currently contains details of 428 ICEs found in representatives of 124 bacterial species, and a collection of >400 directly related references. A broad range of similarity search, sequence alignment, genome context browser, phylogenetic and other functional analysis tools are readily accessible via ICEberg. We propose that ICEberg will facilitate efficient, multi-disciplinary and innovative exploration of bacterial ICEs and be of particular interest to researchers in the broad fields of prokaryotic evolution, pathogenesis, biotechnology and metabolism. The ICEberg database will be maintained, updated and improved regularly to ensure its ongoing maximum utility to the research community.