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学者姓名：李金宇
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Abstract ：
Despite the expansive applications of gas-phase unfolding techniques, the molecular mechanism for the solvent-free forced unfolding pathway which substrate multidomain proteins usually adopt remains elusive at the secondary structure level. Herein, upon carefully selecting CRM197 as a therapeutically-relevant model system containing multiple secondary structure-separated domains, we systematically examine its solvent-free unfolding pathway. Further-more, utilizing the hybrid of noncovalent chemical probing with niacinamide and ion mobility-mass spectrometry-guided all-atom molecular dynamics simulations, we map a nearly complete unfolding atlas for the conjugate vaccine carrier protein CRM197 in a domain-and secondary structure-resolved manner. The totality of our data supports the preferential unfolding of the sheet-rich domain, indicating the dynamic transition from beta-sheet to alpha-helix, and demonstrating that helix exhibit comparatively higher stability than beta-sheets. We propose that this sheet-to-helix dynamic transition may be central to the gas-phase unfolding pathways of multidomain proteins, suggesting the need for systematic studies on additional multidomain protein systems. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Keyword ：
Collision-induced unfolding Collision-induced unfolding CRM197 CRM197 Ion mobility-mass spectrometry Ion mobility-mass spectrometry Molecular dynamics simulation Molecular dynamics simulation Sheet-to-helix transition Sheet-to-helix transition
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| GB/T 7714 | Xu, Xia , Yang, Guiqian , Zheng, Zhen et al. The sheet-to-helix transition is a potential gas-phase unfolding pathway for a multidomain protein CRM197 [J]. | CHINESE CHEMICAL LETTERS , 2025 , 36 (7) . |
| MLA | Xu, Xia et al. "The sheet-to-helix transition is a potential gas-phase unfolding pathway for a multidomain protein CRM197" . | CHINESE CHEMICAL LETTERS 36 . 7 (2025) . |
| APA | Xu, Xia , Yang, Guiqian , Zheng, Zhen , Wenthur, Cody J. , Li, Jinyu , Li, Gongyu . The sheet-to-helix transition is a potential gas-phase unfolding pathway for a multidomain protein CRM197 . | CHINESE CHEMICAL LETTERS , 2025 , 36 (7) . |
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BACKGROUND:FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.METHODS:A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.RESULTS:Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (half maximal inhibitory concentration of 0.17 mu mol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.CONCLUSIONS:This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.
Keyword ：
anticoagulants anticoagulants factor XI factor XI mice mice montelukast montelukast thrombosis thrombosis
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| GB/T 7714 | Zhou, Yang , Wang, Dong , Wu, Juhong et al. Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice [J]. | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY , 2025 , 45 (4) : e150-e162 . |
| MLA | Zhou, Yang et al. "Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice" . | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 45 . 4 (2025) : e150-e162 . |
| APA | Zhou, Yang , Wang, Dong , Wu, Juhong , Qi, Yingying , Song, Meiru , Yao, Huiqiao et al. Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice . | ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY , 2025 , 45 (4) , e150-e162 . |
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The two effectors LnaB and MavL of Legionella pneumophila coordinate the conversion of phosphoribosyl ubiquitin (PR-Ub) released by reversal of ubiquitination induced by members of the SidE effector family into functional Ub. LnaB acts as an actin-dependent phosphoryl AMPylase that converts PR-Ub into ADP-ribosylated (ADPR)-Ub. Catalysis by LnaB requires the conserved SHE motif present in a large family of bacterial toxins. Here we describe a series of structures of LnaB in complex with the cofactor actin and the substrate PR-Ub and ATP. LnaB harbors both adenylyltransferase and ATPase activities, which reveal an adenylylation mechanism involved in a two-step catalytic process. Actin performs a unique activation mechanism that promotes the recruitment of PR-Ub by LnaB to activate LnaB's ATPase activity through interacting with LnaB and PR-Ub. Mechanisms derived from this series of structures covering the process of LnaB action establish an important biochemical basis for protein AMPylation.
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| GB/T 7714 | Chen, Tao-Tao , Lu, Qiuhua , Zheng, Si-Ru et al. Structure and mechanism of an actin-dependent bacterial phosphoryl AMPylase [J]. | NATURE CHEMICAL BIOLOGY , 2025 . |
| MLA | Chen, Tao-Tao et al. "Structure and mechanism of an actin-dependent bacterial phosphoryl AMPylase" . | NATURE CHEMICAL BIOLOGY (2025) . |
| APA | Chen, Tao-Tao , Lu, Qiuhua , Zheng, Si-Ru , Fu, Jiaqi , Chen, Jing , Kang, Lina et al. Structure and mechanism of an actin-dependent bacterial phosphoryl AMPylase . | NATURE CHEMICAL BIOLOGY , 2025 . |
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Antimicrobial peptides (AMPs) are powerful tools in combating drug-resistant bacteria. However, their clinical application is hindered by poor pharmacokinetics and suboptimal antimicrobial activity. This study proposes a strategy to enhance the antimicrobial activity and biosafety of AMPs by modification with albumin-binding molecules (ABMs). This strategy was validated by employing two model peptides with moderate antimicrobial efficacy. First, ABM modification stabilizes the secondary structures, facilitating bacterial membrane disruption. Additionally, modified AMPs target albumin in blood vessels, reducing renal clearance in vivo. Moreover, this binding minimizes contact with blood and endothelial cells, consequently diminishing vascular toxicity without compromising antimicrobial activity. Molecular dynamic simulations followed by experimental validation revealed new molecular insights into the mechanism underlying AMP-mediated membrane disruption, confirming our design strategy. This dual mechanism, structural stabilization and albumin-mediated pharmacokinetic enhancement, addresses the key limitation of AMPs, offering a versatile approach to develop potent, systemically safe antimicrobial therapies.
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| GB/T 7714 | Zhou, Yang , Wu, Juhong , Lin, Haili et al. Modifying Antimicrobial Peptides with Albumin-Binding Molecules Enhances Membrane-Disrupting Efficacy by Modulating the Secondary Structure [J]. | JOURNAL OF MEDICINAL CHEMISTRY , 2025 , 68 (12) : 12658-12674 . |
| MLA | Zhou, Yang et al. "Modifying Antimicrobial Peptides with Albumin-Binding Molecules Enhances Membrane-Disrupting Efficacy by Modulating the Secondary Structure" . | JOURNAL OF MEDICINAL CHEMISTRY 68 . 12 (2025) : 12658-12674 . |
| APA | Zhou, Yang , Wu, Juhong , Lin, Haili , Song, Meiru , Deng, Lina , Mai, Yuhan et al. Modifying Antimicrobial Peptides with Albumin-Binding Molecules Enhances Membrane-Disrupting Efficacy by Modulating the Secondary Structure . | JOURNAL OF MEDICINAL CHEMISTRY , 2025 , 68 (12) , 12658-12674 . |
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Urease, a multifunctional enzyme that catalyzes the hydrolysis of urea into ammonia, plays a pivotal role in nitrogen metabolism across diverse organisms. While essential for survival, its unregulated activity is implicated in numerous pathologies, including peptic ulcers, nephropathy, and gastric cancer, as well as agricultural challenges such as soil ammonium depletion and reduced nitrogen-use efficiency. Beyond its canonical enzymatic function, urease engages in protein-protein interactions with bioactive counterparts like jaburetox, canatoxin, and soyuretox plant-derived proteins with insecticidal, antifungal, and membranolytic properties. Exploring the relationship between ureases and these proteins, along with their mechanistic synergies, presents novel opportunities to develop targeted inhibitors for urease-related diseases while unlocking broader therapeutic and biotechnological applications. This review delves into the dual roles of ureases in plants and humans, bridging the gap between their ureolytic and non-ureolytic activities. We highlight recent advances in the design of urease inhibitors, which have emerged as critical tools for managing pathologies such as Helicobacter pyloriinduced ulcers and urease-mediated kidney stone formation. These inhibitors also hold transformative potential in agriculture, where they mitigate nitrogen loss by stabilizing urea fertilizers, thereby enhancing crop yields and reducing environmental pollution. Furthermore, their utility extends to industrial biotechnology, including biofilm disruption and wastewater treatment, where urease inhibition prevents microbially induced corrosion and ammonia toxicity. The collected information is anticipated to offer insightful guidance and effective strategies for developing novel potent and safe urease inhibitors in the future.
Keyword ：
Multifunctional proteins Multifunctional proteins Pathogenesis Pathogenesis Plant defense Plant defense Urea hydrolysis Urea hydrolysis Urease inhibitors Urease inhibitors
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| GB/T 7714 | Khan, Majid , Zhang, Bo , Zhang, Han et al. Ureases in nature: Multifaceted roles and implications for plant and human health - A review [J]. | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2025 , 306 . |
| MLA | Khan, Majid et al. "Ureases in nature: Multifaceted roles and implications for plant and human health - A review" . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 306 (2025) . |
| APA | Khan, Majid , Zhang, Bo , Zhang, Han , Wu, Juhong , Gao, Ping , Li, Jinyu . Ureases in nature: Multifaceted roles and implications for plant and human health - A review . | INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES , 2025 , 306 . |
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The angiopoietin (Ang)-Tie axis, critical for endothelial cell function and vascular development, is a promising therapeutic target for treating vascular disorders and inflammatory conditions like sepsis. This study aimed to enhance the binding affinity of recombinant Ang1 variants to the Tie2 and explore their therapeutic potential. Structural insights from the Ang1-Tie2 complex enabled the identification of key residues within the Ang1 receptor binding domain (RBD) critical for Tie2 interaction. Molecular dynamics simulations revealed that Met436Arg (M436R) and Ala451Asp (A451D) could improve Ang1's Tie2 binding affinity. One variant, Ang1-RBDA451D, demonstrated a 100-fold increase compared to the wild type. Cellular assays revealed that Ang1A451D enhanced Tie2 phosphorylation, promoting endothelial cell migration and tube formation. In vivo, this variant effectively reduced inflammatory cytokines and attenuated organ damage in septic mice. These findings highlight Ang1A451D as a promising therapeutic candidate for vascular diseases, offering notable clinical potential for mitigating sepsis-related vascular dysfunction.
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| GB/T 7714 | Wang, Rui , Li, Hao , Xie, Zhinuo et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice [J]. | SCIENCE ADVANCES , 2025 , 11 (3) . |
| MLA | Wang, Rui et al. "Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice" . | SCIENCE ADVANCES 11 . 3 (2025) . |
| APA | Wang, Rui , Li, Hao , Xie, Zhinuo , Huang, Meijuan , Xu, Peng , Yuan, Cai et al. Development of a recombinant Ang1 variant with enhanced Tie2 binding and its application to attenuate sepsis in mice . | SCIENCE ADVANCES , 2025 , 11 (3) . |
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The development of RNA interference (RNAi) therapy offers a potential solution for Alzheimer's disease (AD). However, the brain-blood barrier (BBB) with its selective permeability and pharmacokinetic-related challenges poses restrictions on the delivery of small interfering RNA (siRNA) to the central nervous system (CNS). In this study, we demonstrate that the incorporation of 2 '-fluoro (2 '-F) substitutions and L-carnitine modification facilitates the self-assembly of siRNA through triple interaction, leading to the formation of nanorings, called LCSF-NR. Based on the enhanced cellular uptake and lysosomal escape by 2 '-F substitution and the transport across the BBB promoted by L-carnitine, the nanorings realized the improved brain-targeted delivery of siRNA, both in zebrafish and mice models. Moreover, our findings highlight the therapeutic potential of LCSF-NR formulation in an AD zebrafish model through a synergistic effect of downregulating the beta-site APP cleavage enzyme 1 (BACE1) gene and L-carnitine-mediated neuroprotection, effectively inhibiting pathological processes. Overall, these results suggest that the chemical modification-based siRNA self-assembly strategy enables trans-BBB delivery and presents a concise approach for synergistic therapy of AD.
Keyword ：
Alzheimer's disease Alzheimer's disease blood-brain barrier blood-brain barrier chemical modification chemical modification self-assembly self-assembly siRNA siRNA
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| GB/T 7714 | Jiang, Yifan , Li, Lisha , Fang, Xiao et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease [J]. | SCIENCE CHINA-CHEMISTRY , 2025 , 68 (6) : 2552-2564 . |
| MLA | Jiang, Yifan et al. "Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease" . | SCIENCE CHINA-CHEMISTRY 68 . 6 (2025) : 2552-2564 . |
| APA | Jiang, Yifan , Li, Lisha , Fang, Xiao , Zeng, Tao , Su, Lichao , Liu, Yichang et al. Self-assembling chemically modified siRNA nanorings for RNAi therapy and neuroprotection in Alzheimer's disease . | SCIENCE CHINA-CHEMISTRY , 2025 , 68 (6) , 2552-2564 . |
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Water transport across biological membranes is essential for life, facilitated by water channel proteins like aquaporins (AQPs). Drawing inspiration from these natural systems, artificial water channels (AWCs) have emerged as transformative tools for advancing industrial and environmental applications. Herein, we report the design and comprehensive characterization of a groundbreaking class of AWCs, derived from unprecedented butterfly-shaped aromatic folding synthons, carefully engineered to emulate the functional attributes of natural AQPs. These foldamers, with their intricate helical architectures, exhibit exceptional water transport performance. Remarkably, the highest-performing AWC achieves an ultrafast water transport rate of 2.6 × 1010 H2O s−1 per channel—2.4 times the efficiency of AQP1—without the need for lipid anchors to preserve its functional orientation within phospholipid bilayers, while effectively excluding salts such as NaCl and KCl, along with protons. This work presents an ideal bio-inspired, high-performance artificial alternative to natural systems, demonstrating the remarkable potential of foldamer-based AWCs as next-generation solutions for tackling critical challenges in water purification and desalination. © 2025 Wiley-VCH GmbH.
Keyword ：
Artificial water channels Artificial water channels Proton rejection Proton rejection Salt rejection Salt rejection Supramolecular chemistry Supramolecular chemistry Water desalination Water desalination
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| GB/T 7714 | Shen, J. , Zhang, Y. , Jin, Y. et al. Butterfly-Shaped Folding Synthons for Designing Superselective and Ultrapermeable Artificial Water Channels [J]. | Angewandte Chemie - International Edition , 2025 . |
| MLA | Shen, J. et al. "Butterfly-Shaped Folding Synthons for Designing Superselective and Ultrapermeable Artificial Water Channels" . | Angewandte Chemie - International Edition (2025) . |
| APA | Shen, J. , Zhang, Y. , Jin, Y. , Zhou, Z.-X. , Xu, Y. , Chang, W. et al. Butterfly-Shaped Folding Synthons for Designing Superselective and Ultrapermeable Artificial Water Channels . | Angewandte Chemie - International Edition , 2025 . |
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Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD+)-bound SPARSA with and without nucleic acids at resolutions of 3.1 angstrom and 3.6 angstrom, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD+ binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD+ hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system. Short prokaryotic Argonaute and Sir2 proteins function as an antivirus system. Here the authors describe structures of SPARSA (a heterodimer of Sir2-APAZ and prokaryotic Argonaute) with and without template DNA and guide RNA, providing structural basis of its assembly and activation by the recognition of the invading virus.
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| GB/T 7714 | Zhen, Xiangkai , Xu, Xiaolong , Ye, Le et al. Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system [J]. | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
| MLA | Zhen, Xiangkai et al. "Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system" . | NATURE COMMUNICATIONS 15 . 1 (2024) . |
| APA | Zhen, Xiangkai , Xu, Xiaolong , Ye, Le , Xie, Song , Huang, Zhijie , Yang, Sheng et al. Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system . | NATURE COMMUNICATIONS , 2024 , 15 (1) . |
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The transport behaviors of aqueous solution in two-dimensional (2D) nanomaterial-based separation membranes are correlated with the structure of the nanoconfined geometry. However, little is known about the impact of asymmetric structures on the transport behavior of aqueous solutions in membranes. In this work, we use molecular dynamics (MD) simulations to investigate the transport behaviors of aqueous solution in non-parallel stacked graphitic carbon nitride (g-C3N4) nanochannels. Interestingly, the non-parallel stacking of g-C3N4 could lead to the local aggregation of water, resulting in an inhomogeneous density distribution within the nanochannel. The high-density region in g-C3N4 nanochannel significantly disrupted the continuum fluid of water. Moreover, the inhomogeneous density distribution of water could impede ion transport in the non-parallel g-C3N4 nanochannel. It was found that ions cannot maintain compact hydration structures in the high-density region. This work reveals the unique properties of slightly tilted membrane structures, providing novel perspective for the design of next-generation nanofluidic devices.
Keyword ：
Desalination Desalination Graphitic carbon nitride Graphitic carbon nitride Inhomogeneous confined structure Inhomogeneous confined structure Molecular dynamics Molecular dynamics Two-dimensional nanochannel Two-dimensional nanochannel
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| GB/T 7714 | Liu, Yichang , Zou, Yujin , Zhu, Hao et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study [J]. | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
| MLA | Liu, Yichang et al. "Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study" . | JOURNAL OF MOLECULAR LIQUIDS 396 (2024) . |
| APA | Liu, Yichang , Zou, Yujin , Zhu, Hao , Xie, Song , Wu, Juhong , Li, Jinlong et al. Effect of inhomogeneous structure on the water desalination performance of graphitic carbon nitride nanochannels: A molecular dynamics study . | JOURNAL OF MOLECULAR LIQUIDS , 2024 , 396 . |
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