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学者姓名：李金宇
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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 rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has led to over 600 million cases of coronavirus disease 2019 (COVID-19). Identifying effective molecules that can counteract the virus is imperative. SARS-CoV-2 macrodomain 1 (Mac1) represents a promising antiviral drug target. In this study, we predicted potential inhibitors of SARS-CoV-2 Mac1 from natural products using in silico-based screening. Based on the high-resolution crystal structure of Mac1 bound to its endogenous ligand ADP-ribose (ADPr), we first performed a docking-based virtual screening of Mac1 inhibitors against a natural product library and obtained five representative compounds (MC1–MC5) by clustering analysis. All five compounds were stably bound to Mac1 during 500 ns long molecular dynamics simulations. The binding free energy of these compounds to Mac1 was calculated using molecular mechanics generalized Born surface area and further refined with localized volume-based metadynamics. The results demonstrated that both MC1 (−9.8 ± 0.3 kcal/mol) and MC5 (−9.6 ± 0.3 kcal/mol) displayed more favorable affinities to Mac1 with respect to ADPr (−8.9 ± 0.3 kcal/mol), highlighting their potential as potent SARS-CoV-2 Mac1 inhibitors. Overall, this study provides potential SARS-CoV-2 Mac1 inhibitors, which may pave the way for developing effective therapeutics for COVID-19. Communicated by Ramaswamy H. Sarma
Keyword ：
COVID-19 COVID-19 inhibitor inhibitor macrodomain macrodomain MD simulation MD simulation metadynamics metadynamics SARS-CoV-2 SARS-CoV-2
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| GB/T 7714 | Song Xie , Shoujing Cao , Juhong Wu et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 [J]. | Journal of Biomolecular Structure and Dynamics , 2024 , 42 (10) : 5229-5237 . |
| MLA | Song Xie et al. "In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1" . | Journal of Biomolecular Structure and Dynamics 42 . 10 (2024) : 5229-5237 . |
| APA | Song Xie , Shoujing Cao , Juhong Wu , Zhinuo Xie , Yu-Tsen Liu , Wei Fu et al. In silico-based screening of natural products as potential inhibitors of SARS-CoV-2 macrodomain 1 . | Journal of Biomolecular Structure and Dynamics , 2024 , 42 (10) , 5229-5237 . |
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The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (& sdot;OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc ), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metalcoordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.
Keyword ：
Chemodynamical therapy Chemodynamical therapy Ferroptosis Ferroptosis Immunotherapy Immunotherapy Metal -coordinated nanoplatform Metal -coordinated nanoplatform Synergistic chemotherapy Synergistic chemotherapy
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| GB/T 7714 | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu et al. Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis [J]. | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 : 257-276 . |
| MLA | Zhao, Rui-Rui et al. "Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis" . | JOURNAL OF COLLOID AND INTERFACE SCIENCE 660 (2024) : 257-276 . |
| APA | Zhao, Rui-Rui , Wu, Ju-Hong , Li, Jin -Yu , Lu, Yu-sheng , Shao, Jing -Wei . Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis . | JOURNAL OF COLLOID AND INTERFACE SCIENCE , 2024 , 660 , 257-276 . |
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Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (12) and L-3-(N-amidino-4-piperidyl)alanine (16), as novel P1 residues in peptide inhibitors. 16 notably enhances affinities across all tested proteases, whereas 12 specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of 12 towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases. © 2024 Elsevier Inc.
Keyword ：
P1 residue P1 residue Peptide inhibitors Peptide inhibitors S1 pocket S1 pocket Serine protease Serine protease Specificity Specificity
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| GB/T 7714 | Lin, H. , Xu, M. , Jiang, L. et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue [J]. | Bioorganic Chemistry , 2024 , 152 . |
| MLA | Lin, H. et al. "Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue" . | Bioorganic Chemistry 152 (2024) . |
| APA | Lin, H. , Xu, M. , Jiang, L. , Yuan, C. , Jiang, C. , Huang, M. et al. Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue . | Bioorganic Chemistry , 2024 , 152 . |
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Proper chromosome segregation during cell division relies on the timely dissolution of chromosome cohesion. Separase (EC 3.4.22.49), a cysteine protease, plays a critical role in mitosis by cleaving the kleisin subunit of cohesin, thereby presenting a promising target for cancer therapy. However, challenges in isolating active human separase suitable for high-throughput screening have limited the identification of effective inhibitors. Here, we conducted a high-throughput screening of small-molecule inhibitors using the protease domain of Chaetomium thermophilum separase (ctSPD), which not only shares significant sequence similarity with human separase but is also readily available. After conducting a primary screening of a library containing 9,172 compounds and subsequent validation using human separase, we identified walrycin B and its analogs, toxoflavin, 3-methyltoxoflavin, and 3-phenyltoxoflavin, as potent inhibitors of human separase. Subsequent microscale thermophoresis assays and molecular dynamics simulations revealed that walrycin B binds to the active site of separase and competes with substrates for binding. Additionally, cell-based studies showed that walrycin B and its analogs effectively induce cell cycle arrest at the M phase, activate apoptosis, and ultimately lead to cell death in mitosis. Finally, in a mouse xenograft model, walrycin B exhibited significant antitumor efficacy with minimal side effects. Together, these findings highlight the therapeutic potential of walrycin B for cancer treatment and its utility as a chemical tool in future studies involving separase. © 2024 Elsevier Inc.
Keyword ：
Anticancer Anticancer Inhibitor Inhibitor Separase Separase Toxoflavin Toxoflavin Walrycin B Walrycin B
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| GB/T 7714 | Zhu, Q. , Du, L. , Wu, J. et al. Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model [J]. | Biochemical Pharmacology , 2024 , 229 . |
| MLA | Zhu, Q. et al. "Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model" . | Biochemical Pharmacology 229 (2024) . |
| APA | Zhu, Q. , Du, L. , Wu, J. , Li, J. , Lin, Z. . Walrycin B, as a novel separase inhibitor, exerts potent anticancer efficacy in a mouse xenograft model . | Biochemical Pharmacology , 2024 , 229 . |
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l-Tryptophan decarboxylase (TDC) and l-3,4-dihydroxyphenylalanine decarboxylase (DDC) catalyze the decarboxylation of l-tryptophan, 5-hydroxytryptophan, and l-3,4-dihydroxyphenylalanine. In this study, we analyzed the amino acid compositions of the substrate-binding pockets of TDC from Catharanthus roseus (CrTDC) and DDC from Sus scrofa (SsDDC), explored the specificity of key amino acids within these pockets, and elucidated mechanisms influencing substrate selectivity and catalytic activity in both enzymes, using whole-cell catalysis to screen mutants and determine enzymatic kinetic parameters. The results demonstrated that residues Ala-103 and Val-122 in CrTDC, along with their corresponding sites Thr-82 and Ile-101 in SsDDC, significantly influence substrate selectivity and catalytic efficiency. Molecular dynamics simulations revealed that substrate selectivity and catalytic efficiency depends on the nucleophilic attack distance between the substrate's amino group and the C4 ' of pyridoxal 5 '-phosphate. This study elucidates the catalytic mechanisms and structural bases of TDC and DDC, guiding enhancements in the related aromatic monoamine biosynthesis.
Keyword ：
catalytic efficiency catalytic efficiency CrTDC CrTDC moleculardynamics moleculardynamics SsDDC SsDDC substrate selectivity substrate selectivity
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| GB/T 7714 | Liu, Qinghao , Wu, Juhong , Chen, Maosen et al. Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases [J]. | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY , 2024 , 72 (48) : 26996-27006 . |
| MLA | Liu, Qinghao et al. "Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases" . | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 72 . 48 (2024) : 26996-27006 . |
| APA | Liu, Qinghao , Wu, Juhong , Chen, Maosen , Zhong, Jie , Huang, Jianzhong , Wang, Bingmei et al. Unraveling the Molecular Determinants of Catalytic Efficiency and Substrate Specificity in l-Amino Acid Decarboxylases . | JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY , 2024 , 72 (48) , 26996-27006 . |
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The combination of infrared spectroscopy (IR) and ion mobility mass spectrometry (IM-MS) has revealed that protein secondary structures are retained upon transformation from aqueous solution to the gas phase under gentle conditions. Yet the details about where and how these structural elements are embedded in the gas phase remain elusive. In this study, we employ long time scale molecular dynamics (MD) simulations to examine the extent to which proteins retain their solution structures and the impact of protonation state on the stability of secondary structures in the gas phase. Our investigation focuses on two well-studied proteins, myoglobin and beta-lactoglobulin, representing typical helical and beta-sheet proteins, respectively. Our simulations accurately reproduce the experimental collision cross section (CCS) data measured by IM-MS. Based on accurately reproducing previous experimental collision cross section data and dominant secondary structural species obtained from IM-MS and IR, we confirm that both proteins largely retain their native secondary structural components upon passing from aqueous solution to the gas phase. However, we observe significant reductions in secondary structure contents (19.2 +/- 1.2% for myoglobin and 7.3 +/- 0.6% for beta-lactoglobulin) in specific regions predominantly composed of ionizable residues. Further mechanistic analysis suggests that alterations in protonation states of these residues after phase transition induce changes in their local interaction networks and backbone dihedral angles, which potentially promote the unfolding of secondary structures in the gas phase. We anticipate that similar protonation state induced unfolding may be observed in other proteins possessing distinct secondary structures. Further studies on a broader array of proteins will be essential to refine our understanding of protein structural behavior during the transition to the gas phase.
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| GB/T 7714 | Yang, Guiqian , Zhang, Lanbi , Xie, Song et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase [J]. | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) : 9374-9379 . |
| MLA | Yang, Guiqian et al. "Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase" . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS 15 . 37 (2024) : 9374-9379 . |
| APA | Yang, Guiqian , Zhang, Lanbi , Xie, Song , Wu, Juhong , Khan, Majid , Zhang, Yongqi et al. Protonation State-Induced Unfolding of Protein Secondary Structure in the Gas Phase . | JOURNAL OF PHYSICAL CHEMISTRY LETTERS , 2024 , 15 (37) , 9374-9379 . |
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The urokinase-type plasminogen activator receptor (uPAR) emerges as a key target for anti-metastasis owing to its pivotal role in facilitating the invasive and migratory processes of cancer cells. Recently, we identified the uPAR-targeting anti-metastatic ability of diltiazem (22), a commonly used antihypertensive agent. Fine-tuning the chemical structures of known hits represents a vital branch of drug development. To develop novel anti-metastatic drugs, we performed an interface-driven structural evolution strategy on 22. The uPAR-targeting and anti-cancer abilities of this antihypertensive drug wereidentified by us recently. Based on in silico strategy, including extensive molecular dynamics (MD) simulations, hierarchical binding free energy predictions, and ADMET profilings, we designed, synthesized, and identified three new diltiazem derivatives (221-8, 221-57, and 221-68) as uPAR inhibitors. Indeed, all of these three derivatives exhibited uPAR-depending inhibitory activity against PC-3 cell line invasion at micromolar level. Particularly, derivatives 221-68 and 221-8 showed enhanced uPAR-dependent inhibitory activity against the tumor cell invasion compared to the original compound. Microsecond timesclae MD simulations demonstrated the optimized moiety of 221-68 and 221-8 forming more comprehensive interactions with the uPAR, highlighting the reasonability of our strategy. This work introduces three novel uPAR inhibitors, which not only pave the way for the development of effective anti-metastatic therapeutics, but also emphasize the efficacy and robustness of an in silico-based lead compound optimization strategy in drug design. Graphical abstract: (Figure presented.) © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.
Keyword ：
Anti-metastasis Anti-metastasis Metadynamics Metadynamics Molecular dynamics simulation Molecular dynamics simulation uPAR inhibitors uPAR inhibitors
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| GB/T 7714 | Xie, S. , Zhou, Y. , Zhu, H. et al. Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation [J]. | Molecular Diversity , 2024 . |
| MLA | Xie, S. et al. "Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation" . | Molecular Diversity (2024) . |
| APA | Xie, S. , Zhou, Y. , Zhu, H. , Xu, X. , Zhang, H. , Yuan, C. et al. Interface-driven structural evolution on diltiazem as novel uPAR inhibitors: from in silico design to in vitro evaluation . | Molecular Diversity , 2024 . |
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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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Sialylation, a critical post-translational modification, regulates glycoprotein structure and function by tuning their molecular heterogeneity. However, characterizing its subtle and dynamic conformational effects at the intact glycoprotein level remains challenging. We introduce a glycoform-resolved unfolding approach based on a high-throughput ion mobility-mass spectrometry (IM-MS) platform. This method integrates high-throughput unfolding with parallel fragmentation, enabling simultaneous analysis of sialylation patterns, stoichiometries, and their impact on conformational stability. Applying this approach to fetuin, we identified distinct sialylation patterns and their differential influence on protein conformation, namely sialylation-induced stabilization during early unfolding and increased flexibility in later unfolding stages. IM-MS-guided molecular dynamics simulations revealed that increased sialylation enhances the initial conformational stability, likely through enhanced electrostatic interactions and hydrogen bonding. These findings highlight the complex interplay between sialylation and protein dynamics and establish glycoform-resolved unfolding IM-MS as a powerful tool for characterizing glycoprotein conformational landscapes. © 2024 The Royal Society of Chemistry.
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| GB/T 7714 | Jia, Y. , Liu, Y. , Wang, Y. et al. Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry [J]. | Chemical Science , 2024 , 15 (35) : 14431-14439 . |
| MLA | Jia, Y. et al. "Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry" . | Chemical Science 15 . 35 (2024) : 14431-14439 . |
| APA | Jia, Y. , Liu, Y. , Wang, Y. , Li, J. , Li, G. . Sialylation-induced stabilization of dynamic glycoprotein conformations unveiled by time-aligned parallel unfolding and glycan release mass spectrometry . | Chemical Science , 2024 , 15 (35) , 14431-14439 . |
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