Cell Discovery最新文献

The α7 nicotinic acetylcholine receptor (nAChR), a pentameric ligand-gated ion channel, plays important roles in cognition, neuroprotection, and anti-inflammation. As a potential drug target, α7 nAChR has different binding sites for different ligands, particularly agonists and positive allosteric modulators (PAMs). Ago-PAMs can both directly activate and allosterically modulate α7 nAChR. However, the mechanism underlying α7 nAChR modulation by ago-PAM has yet to be fully elucidated. Here, we present cryo-EM structures of α7 nAChR in complex with the ago-PAM GAT107 and Ca²⁺ in the open and desensitized states, respectively. Our results from both structural comparisons and functional assays suggest an allosteric mechanism underlying GAT107 modulation and calcium potentiation of α7 nAChR, involving local conformational changes in the ECD-TMD coupling region and a global structural rearrangement in the transmembrane domain. This work provides a new mechanism of α7 nAChR gating distinct from that of conventional agonist binding. These findings would aid in drug design and enrich our biophysical understanding of pentameric ligand-gated ion channels.

Coxsackievirus B3 (CVB3)-induced acute heart failure (AHF) is a common cause of cardiogenic death in young- and middle-aged people. However, the key molecular events linking CVB3 to AHF remain largely unknown, resulting in a lack of targeted therapy strategies thus far. Here, we unexpectedly found that Viperin deficiency does not promote CVB3 infection but protects mice from CVB3-induced AHF. Importantly, cardiac-specific expression of Viperin can induce cardiac dysfunction. Mechanistically, CVB3-encoded 3C protease rescues Viperin protein expression in cardiomyocytes by lowering UBE4A. Viperin in turn interacts with and reduces STAT1 to activate SGK1-KCNQ1 signaling, and eventually leads to cardiac electrical dysfunction and subsequent AHF. Furthermore, we designed an interfering peptide VS-IP1, which blocked Viperin-mediated STAT1 degradation and therefore prevented CVB3-induced AHF. This study established the first signaling link between CVB3 and cardiac electrical dysfunction, and revealed the potential of interfering peptides targeting Viperin for the treatment of CVB3-induced AHF.

Natural Medicinal Materials (NMMs) have a long history of global clinical applications and a wealth of records and knowledge. Although NMMs are a major source for drug discovery and clinical application, the utilization and sharing of NMM knowledge face crucial challenges, including the standardized description of critical information, efficient curation and acquisition, and language barriers. To address these, we developed ShennongAlpha, an artificial intelligence (AI)-driven sharing and collaboration platform for intelligent knowledge curation, acquisition, and translation. For standardized knowledge curation, the platform introduced a Systematic Nomenclature to enable accurate differentiation and identification of NMMs. More than fourteen thousand Chinese NMMs have been curated into the platform along with their knowledge. Furthermore, the platform pioneered chat-based knowledge acquisition, standardized machine translation, and collaborative knowledge updating. Together, our study represents the first major advance in leveraging AI to empower NMM knowledge sharing, which not only marks a novel application of AI for science, but also will significantly benefit the global biomedical, pharmaceutical, physician, and patient communities.

Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Here, we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with urate in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout.

An outbreak of mpox has triggered concerns regarding the adequacy of intervention strategies. Passive immunity conferred by neutralizing antibodies exhibits potential in the prophylaxis and treatment of orthopoxvirus infections. Despite this, the investigations of effective antibody therapeutics have been hindered by the varied nature of orthopoxvirus envelope proteins and the intricate mechanisms underpinning viral invasion. Our study involves the production of six mpox virus (MPXV) envelope proteins, which are relatively conservative and considered to play a role in the neutralization process. We employed a synthetic nanobody (Nb) library to derive a broad array of specific Nbs against these viral proteins. We identified a cross-reactive Nb, termed M1R-01, which targets the M1R protein and effectively neutralizes both vaccinia virus (VACV) and MPXV. Notably, the M1R-01-based antibody strategy provided optimal protection against a lethal VACV challenge in mice. Additionally, we determined the crystal structure of the M1R-Nb complex, uncovering novel binding attributes of M1R-01 and detailed conformational epitope information. This work provides a promising candidate for the therapy and prophylaxis of orthopoxvirus infections.

The cGAS-STING pathway mediates the innate immune response to cytosolic DNA, contributing to surveillance against microbial invasion or cellular damage. Once activated, STING recruits TBK1 at the trans-Golgi network (TGN), which in turn phosphorylates IRF3 to induce type I interferon (IFN-I) expression. In contrast to STING, little is known about how TBK1 is transported to the TGN for activation. Here, we show that multiple TGN tethering factors, a group of proteins involved in vesicle capturing, are indispensable for STING-IFN-I signaling. Deletion of TBC1D23, a recently reported tethering factor, in mice impairs the STING-IFN-I signaling, but with insignificant effect on STING-NF-κB signaling. Mechanistically, TBC1D23 interacts with TBK1 via the WASH complex subunit FAM21 and promotes its endosome-to-TGN translocation. Furthermore, multiple TGN tethering factors were reduced in aged mice and senescent fibroblasts. In summary, our study uncovers that TGN tethering factors are key regulators of the STING-IFN-I signaling and suggests that their reduction in senescence may produce aberrant STING signaling.

Spermatogenesis is an intricate and tightly controlled process encompassing various layers of gene expression regulation. Despite the advance of our current understanding, the developmental trajectory and regulatory mechanisms dictating spermatogenesis remain elusive. In this study, we have generated single-cell gene expression profiles for Caenorhabditis elegans sperm cells and constructed gene regulatory networks alongside the developmental trajectories of these cells. Our findings indicate that each pre- and post-developmental stage is closely linked by co-expressed genes, while simultaneously being uniquely identified by the combined expression of specific gene families. To illustrate the applicability of this exhaustive gene expression catalog, we used gene regulatory networks to uncover potential transcription factors for (1) the expression of genes in the phosphorylation pathway, identifying NHR-23-to-phosphatase regulation for the meiotic cell division process; and (2) the expression of constituent components of small RNA pathways, identifying ELT-1-to-Argonaute protein regulation for siRNA maintenance and sperm activation. We expect that this sperm cell-specific gene expression directory will prompt investigations into the underlying mechanisms determining anatomy, differentiation, and function across the reproductive system. Finally, our expression data can be explored using the web application CelegansGermAtlas ( https://scgerm-atlas.sjtu.edu.cn/website/#/home ).