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The Druggable Transcriptome Project: From Chemical Probes to Precision Medicines 可药物转录组计划:从化学探针到精密药物
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-25 DOI: 10.1021/acs.biochem.5c0000610.1021/acs.biochem.5c00006
Matthew D. Disney*, 
{"title":"The Druggable Transcriptome Project: From Chemical Probes to Precision Medicines","authors":"Matthew D. Disney*,&nbsp;","doi":"10.1021/acs.biochem.5c0000610.1021/acs.biochem.5c00006","DOIUrl":"https://doi.org/10.1021/acs.biochem.5c00006https://doi.org/10.1021/acs.biochem.5c00006","url":null,"abstract":"<p >RNA presents abundant opportunities as a drug target, offering significant potential for small molecule medicine development. The transcriptome, comprising both coding and noncoding RNAs, is a rich area for therapeutic innovation, yet challenges persist in targeting RNA with small molecules. RNA structure can be predicted with or without experimental data, but discrepancies with the actual biological structure can impede progress. Prioritizing RNA targets supported by genetic or evolutionary evidence enhances success. Further, small molecules must demonstrate binding to RNA in cells, not solely in vitro, to validate both the target and compound. Effective small molecule binders modulate functional sites that influence RNA biology, as binding to nonfunctional sites requires recruiting effector mechanisms, for example degradation, to achieve therapeutic outcomes. Addressing these challenges is critical to unlocking RNA’s vast potential for small molecule medicines, and a strategic framework is proposed to navigate this promising field, with a focus on targeting human RNAs.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 8","pages":"1647–1661 1647–1661"},"PeriodicalIF":2.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genome-Wide Analysis of Stable RNA Secondary Structures across Multiple Organisms Using Chemical Probing Data: Insights into Short Structural Motifs and RNA-Targeting Therapeutics. 使用化学探测数据对多种生物的稳定RNA二级结构进行全基因组分析:对短结构基序和RNA靶向治疗的见解。
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-25 DOI: 10.1021/acs.biochem.4c00764
Jingxin Wang
{"title":"Genome-Wide Analysis of Stable RNA Secondary Structures across Multiple Organisms Using Chemical Probing Data: Insights into Short Structural Motifs and RNA-Targeting Therapeutics.","authors":"Jingxin Wang","doi":"10.1021/acs.biochem.4c00764","DOIUrl":"10.1021/acs.biochem.4c00764","url":null,"abstract":"<p><p>Small molecules targeting specific RNA-binding sites, including stable and transient RNA structures, are emerging as effective pharmacological approaches for modulating gene expression. However, little is understood about how stable RNA secondary structures are shared across organisms, which is an important factor in controlling drug selectivity. In this study, I provide an analytical pipeline named RNA secondary structure finder (R2S-Finder) to discover short, stable RNA structural motifs in humans, <i>Escherichia coli</i> (<i>E. coli</i>), SARS-CoV-2, and Zika virus by leveraging existing in vivo and in vitro genome-wide chemical RNA-probing datasets. I found several common features across the organisms. For example, apart from the well-documented tetraloops, AU-rich tetraloops are widely present in different organisms. I also validated that the 5' untranslated region (UTR) contains a higher proportion of stable structures than the coding sequences in humans and Zika virus. In general, stable structures predicted from in vitro (protein-free) and in vivo datasets are consistent across different organisms, indicating that stable structure formation is mostly driven by RNA folding, while a larger variation was found between in vitro and in vivo data for certain RNA types, such as human long intergenic noncoding RNAs (lincRNAs). Finally, I predicted stable three- and four-way RNA junctions that exist under both in vivo and in vitro conditions and can potentially serve as drug targets. All results of stable structures, stem-loops, internal loops, bulges, and <i>n</i>-way junctions have been collated in the R2S-Finder database (https://github.com/JingxinWangLab/R2S-Finder), which is coded in hyperlinked HTML pages and tabulated in CSV files.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Regulatory Genes as Beacons for Discovery and Prioritization of Biosynthetic Gene Clusters in Streptomyces. 调控基因作为链霉菌生物合成基因簇发现和优先排序的信标。
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-25 DOI: 10.1021/acs.biochem.4c00711
Hannah E Augustijn, Daan van Nassauw, Simona Cernat, Zachary L Reitz, Gilles P van Wezel, Marnix H Medema
{"title":"Regulatory Genes as Beacons for Discovery and Prioritization of Biosynthetic Gene Clusters in <i>Streptomyces</i>.","authors":"Hannah E Augustijn, Daan van Nassauw, Simona Cernat, Zachary L Reitz, Gilles P van Wezel, Marnix H Medema","doi":"10.1021/acs.biochem.4c00711","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00711","url":null,"abstract":"<p><p>Actinobacteria are renowned for their ability to produce a wide range of bioactive molecules, including many anticancer compounds and antibiotics that are critical in the battle against antimicrobial resistance. Despite identification of a vast array of biosynthetic gene clusters (BGCs) through genome mining, much of this biosynthetic potential remains unexplored, partially due to the fact that many remain silent or cryptic under typical laboratory conditions. Regulatory networks can provide clues to the location of yet undiscovered gene cluster families or be leveraged to predict their expression. Here, we investigate the associations between regulatory genes and BGCs to uncover their predictive capabilities in discovering and prioritizing gene clusters for downstream wet-lab validation. By analyzing the protein domain architectures of 128,993 potential regulators derived from 440 complete <i>Streptomyces</i> genomes, we uncovered various associations between biosynthetic classes, biological activities of their products, and regulator families. Specifically, subsets of the <i>Streptomyces</i> Antibiotic Regulatory Protein (SARP) and LuxR families were strongly associated with biosynthetic pathways encoding the production of bioactive compounds. After closer genomic inspection of the small SARPs, we discovered 82 putative SARP-associated BGCs that escaped detection by state-of-the-art software. This shows that continued exploration of regulatory systems will not only deepen our understanding of Actinobacteria's biosynthetic capabilities but also facilitates discovery and prioritization of high-potential BGCs in future genome-mining applications.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis 肽聚糖生物合成抑制剂磷霉素的分子药理学研究
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-24 DOI: 10.1021/acs.biochem.4c0052210.1021/acs.biochem.4c00522
Dennis H. Kim*,  and , Watson J. Lees*, 
{"title":"Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis","authors":"Dennis H. Kim*,&nbsp; and ,&nbsp;Watson J. Lees*,&nbsp;","doi":"10.1021/acs.biochem.4c0052210.1021/acs.biochem.4c00522","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00522https://doi.org/10.1021/acs.biochem.4c00522","url":null,"abstract":"<p >The antibiotic fosfomycin is an epoxy-phosphonate natural product with a broad spectrum of antibacterial activity and distinct mechanism of action that has been in clinical use for 50 years. Fosfomycin is an irreversible covalent inhibitor of UDP-GlcNAc enolpyruvyl transferase (MurA), which catalyzes the first committed step in bacterial peptidoglycan biosynthesis. Fosfomycin binds to the active site of MurA in competition with substrate phosphoenolpyruvate (PEP) and undergoes the ring-opening nucleophilic attack of an active-site cysteine. MurA and its related enolpyruvyl transferase, 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase (AroA), are the only known enzymes to catalyze the unusual enolpyruvyl transfer from PEP, and each is the target of an important inhibitor. Specifically, MurA is inactivated by fosfomycin, and EPSP synthase (AroA) of the shikimate pathway is the target of the herbicide glyphosate. Commonalities and differences in enzymatic reaction mechanisms of MurA and EPSP synthase provide a molecular rationale for the specificity of their respective inhibitors. With its distinct mode of molecular action and clinical activity against multidrug-resistant bacteria, fosfomycin continues to motivate the discovery and development of novel inhibitors of MurA.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 8","pages":"1720–1727 1720–1727"},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver 靶向聚合纳米颗粒在肝脏中的特定细胞群
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-24 DOI: 10.1021/acs.biochem.4c0071210.1021/acs.biochem.4c00712
Lauren Harkins, Silvia Vilarinho and W. Mark Saltzman*, 
{"title":"Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver","authors":"Lauren Harkins,&nbsp;Silvia Vilarinho and W. Mark Saltzman*,&nbsp;","doi":"10.1021/acs.biochem.4c0071210.1021/acs.biochem.4c00712","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00712https://doi.org/10.1021/acs.biochem.4c00712","url":null,"abstract":"<p >Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 8","pages":"1685–1697 1685–1697"},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis. 肽聚糖生物合成抑制剂磷霉素的分子药理学研究。
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-24 DOI: 10.1021/acs.biochem.4c00522
Dennis H Kim, Watson J Lees
{"title":"Molecular Pharmacology of the Antibiotic Fosfomycin, an Inhibitor of Peptidoglycan Biosynthesis.","authors":"Dennis H Kim, Watson J Lees","doi":"10.1021/acs.biochem.4c00522","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00522","url":null,"abstract":"<p><p>The antibiotic fosfomycin is an epoxy-phosphonate natural product with a broad spectrum of antibacterial activity and distinct mechanism of action that has been in clinical use for 50 years. Fosfomycin is an irreversible covalent inhibitor of UDP-GlcNAc enolpyruvyl transferase (MurA), which catalyzes the first committed step in bacterial peptidoglycan biosynthesis. Fosfomycin binds to the active site of MurA in competition with substrate phosphoenolpyruvate (PEP) and undergoes the ring-opening nucleophilic attack of an active-site cysteine. MurA and its related enolpyruvyl transferase, 5-enolpyruvyl-shikimate-3-phosphate (EPSP) synthase (AroA), are the only known enzymes to catalyze the unusual enolpyruvyl transfer from PEP, and each is the target of an important inhibitor. Specifically, MurA is inactivated by fosfomycin, and EPSP synthase (AroA) of the shikimate pathway is the target of the herbicide glyphosate. Commonalities and differences in enzymatic reaction mechanisms of MurA and EPSP synthase provide a molecular rationale for the specificity of their respective inhibitors. With its distinct mode of molecular action and clinical activity against multidrug-resistant bacteria, fosfomycin continues to motivate the discovery and development of novel inhibitors of MurA.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver. 靶向聚合纳米颗粒在肝脏中的特定细胞群。
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-24 DOI: 10.1021/acs.biochem.4c00712
Lauren Harkins, Silvia Vilarinho, W Mark Saltzman
{"title":"Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver.","authors":"Lauren Harkins, Silvia Vilarinho, W Mark Saltzman","doi":"10.1021/acs.biochem.4c00712","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00712","url":null,"abstract":"<p><p>Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Functionally Selective Dopamine D1 Receptor Endocytosis and Signaling by Catechol and Noncatechol Agonists 儿茶酚和非儿茶酚激动剂的功能选择性多巴胺D1受体内吞和信号传导
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-20 DOI: 10.1021/acs.biochem.4c0087610.1021/acs.biochem.4c00876
Ashley N. Nilson, Daniel E. Felsing, Pingyuan Wang, Manish K. Jain, Jia Zhou and John A. Allen*, 
{"title":"Functionally Selective Dopamine D1 Receptor Endocytosis and Signaling by Catechol and Noncatechol Agonists","authors":"Ashley N. Nilson,&nbsp;Daniel E. Felsing,&nbsp;Pingyuan Wang,&nbsp;Manish K. Jain,&nbsp;Jia Zhou and John A. Allen*,&nbsp;","doi":"10.1021/acs.biochem.4c0087610.1021/acs.biochem.4c00876","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00876https://doi.org/10.1021/acs.biochem.4c00876","url":null,"abstract":"<p >The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective noncatechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and noncatechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, noncatechol agonists display G protein biased signaling at the D1R and have reduced or absent β-arrestin2 recruitment. A notable exception was compound (Cmpd) 19, a noncatechol agonist with full efficacy at both D1R-G protein and D1R-β-arrestin2 pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R-β-arrestin2 activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The β-arrestin2 super agonist, A-77636, showed statistically significant increases in D1R endocytosis. Moreover, β-arrestin2 recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1572–1588 1572–1588"},"PeriodicalIF":2.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural Insights into Lipoate Ligase A-Mediated Antibody Modifications. 脂酸连接酶a介导的抗体修饰的结构见解。
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-20 DOI: 10.1021/acs.biochem.5c00040
Kazutoshi Takahashi, Shunsuke Yamazaki, Yutaka Matsuda
{"title":"Structural Insights into Lipoate Ligase A-Mediated Antibody Modifications.","authors":"Kazutoshi Takahashi, Shunsuke Yamazaki, Yutaka Matsuda","doi":"10.1021/acs.biochem.5c00040","DOIUrl":"https://doi.org/10.1021/acs.biochem.5c00040","url":null,"abstract":"<p><p>Enzyme-mediated site-specific protein modification is gaining attention in biopharmaceuticals due to its high specificity and mild conditions. Lipoic acid ligase A (LplA) has been widely studied for conjugating short-chain fatty acids to lysine residues, traditionally using LAP tags. Recent advances have enabled tag-free LplA modifications, expanding applications in antibody-drug conjugates (ADCs) and beyond. This study investigates the selective modification of Lys188 in trastuzumab by LplA. Spatial analysis and molecular modeling suggest that D151 and H189 facilitate nucleophilic attack and stabilize intermediates via electrostatic and π-cation interactions. These insights enhance our understanding of enzyme-driven site selectivity, guiding the rational design of antibody modifications. The findings support broader applications in ADC production, diagnostics, and next-generation biopharmaceuticals, emphasizing the role of local amino acid environments in enzymatic modifications.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Charge, Hydrophobicity, and Lipid Type Drive Antimicrobial Peptides’ Unique Perturbation Ensembles 电荷、疏水性和脂质类型驱动抗菌肽独特的微扰集合
IF 2.9 3区 生物学
Biochemistry Biochemistry Pub Date : 2025-03-19 DOI: 10.1021/acs.biochem.4c0045210.1021/acs.biochem.4c00452
Kevin J. Cheng, Shashank Shastry, Juan David Campolargo, Michael J. Hallock and Taras V. Pogorelov*, 
{"title":"Charge, Hydrophobicity, and Lipid Type Drive Antimicrobial Peptides’ Unique Perturbation Ensembles","authors":"Kevin J. Cheng,&nbsp;Shashank Shastry,&nbsp;Juan David Campolargo,&nbsp;Michael J. Hallock and Taras V. Pogorelov*,&nbsp;","doi":"10.1021/acs.biochem.4c0045210.1021/acs.biochem.4c00452","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00452https://doi.org/10.1021/acs.biochem.4c00452","url":null,"abstract":"<p >Antimicrobial peptides (AMPs) have emerged as a promising solution to the escalating public health threat caused by multidrug-resistant bacteria. Although ongoing research efforts have established AMP’s role in membrane permeabilization and leakage, the precise mechanisms driving these disruption patterns remain unclear. We leverage molecular dynamics (MD) simulations enhanced by membrane mimetic (HMMM) to systematically investigate how the physiochemical properties of magainin (+3) and pexiganan (+9) affect their localization, insertion, curvature perturbation, and membrane binding ensemble. Building on existing microbiology, NMR, circular dichroism, and fluorescence data, our analysis reveals that the lipid makeup is a key determinant in the binding dynamics and structural conformation of AMPs. We find that phospholipid type is crucial for peptide localization, demonstrated through magainin’s predominant interaction with lipid tails and pexiganan’s with polar headgroups in POPC/POPS membranes. The membrane curvature changes induced by pexiganan relative to magainin suggest that AMPs with larger charges have more potential in modulating bilayer bending. These insights advance our understanding of AMP–membrane interactions at the molecular level, offering guidance for the design of targeted antimicrobial therapies.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1484–1500 1484–1500"},"PeriodicalIF":2.9,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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