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Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1. GlyT1 critically regulates excitatory neurotransmission and has thus emerged as a therapeutic target for schizophrenia. This study delineates the binding sites of the clinically trialed drugs iclepertin and sarcosine and elucidates how cholesterol modulates GlyT1 activity.

The voltage-gated calcium channel Ca V 1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca V 1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca V 1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca V 1.2 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 S6 II , S6 III , and S6 IV helices and forms extensive hydrophobic interactions with Ca V 1.2. Our structure elucidates that benidipine is located in the D III -D IV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5 DIII , S6 DIII , and S6 DIV 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. CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.

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.

High-voltage-activated R-type Ca V 2.3 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 Ca V 2.3 in complex with the α2δ1 and β1 subunits. The VSD II is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD II 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 S6 II , which is exclusively conserved in the Ca V 2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5 II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca V 2 channels. The Ca V 2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human Ca V 2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.

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.

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.

In this paper, an ultra-broadband flexible polarization-insensitive microwave metamaterial absorber is proposed, characterized, and fabricated. To achieve high broadband absorption, a two-layer periodic indium-tin-oxide (ITO) patches array printed on polyethylene terephthalate (PET) dielectric layers is used to generate high ohmic loss. The simulation results show that the proposed absorber can achieve greater than 90% absorption in the microwave band range of 19.68 to 94.7 GHz. The absorber is polarization-insensitive due to the symmetry of the structure with high absorption over a wide incidence angle of 60°. The mechanism of ultra-broadband absorption is discussed by the impedance matching theory, the surface current distribution, and the electric field distribution. In addition, the equivalent circuit model is utilized to analyze the effect of the structural parameters. Furthermore, the bow-frame method validates that the experimental measurements are consistent with the simulated spectra. With advantages of absorption of ultra-broadband, polarization-insensitivity, and flexibility, the proposed absorber facilitates its use in numerous potential applications for energy harvesting, imaging and sensing, stealth technology, modulating, and so on.

Inhibiting TauT may offer therapeutic potential; however, current inhibitors have not proven effective in treating cancer. [...]gaining more structural insights into TauT could facilitate the development of targeted drugs, ultimately advancing this potential therapy for cancer treatment. Detailed information related to cryo-EM sample preparation, data collection and processing, as well as model building, is provided in Supplementary Materials and Methods. [See PDF for image] Fig. 1 Structural basis of TauT binding with the substrate taurine, the inhibitory substrate β-alanine, and the apo state. a, b The cryo-EM density map of TauTTAU along with the atomic model, displays TM1–TM5 in cyan, TM6–TM10 in purple, and other regions in gray. c Taurine (yellow sticks) is depicted with its corresponding EM density (blue mesh), and the chemical structure is shown on the right. The transmembrane segments TM1a, TM6b, and TM8 form a barrier around the central pocket, sealing it off from the cytoplasm. [...]TM1b, TM6a, TM8, and TM10 obstruct access from the extracellular environment, resulting in an occluded conformation (Fig. 1l).

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 stimulants 1 – 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. Structural analyses of the human dopamine transporter in apo and substrate-bound states and in complex with drugs and inhibitors reveal key binding residues and conformational transitions that occur during substrate transport.

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 neurons 1 – 3 . It is a pharmacological target for various antidepressants and analgesic drugs 4 , 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-MrlA EM ), 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-MrlA EM 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. Cryo-electron microscopy structures of the noradrenaline transporter (NET) reveal binding modes of adrenaline, coordination of sodium and chloride ion binding and the binding sites and mechanisms of inhibition by conotoxin, bupropion and ziprasidone.