Tejaswi Tammareddy, Walid Keyrouz, Ram D. Sriram, Harish C. Pant, Antonio Cardone* and Jeffery B. Klauda*,
{"title":"利用分子模拟研究靶向 CDK5-p25 的多肽 p5 对调控神经元外泌的 Munc18-1 (P67) 的影响","authors":"Tejaswi Tammareddy, Walid Keyrouz, Ram D. Sriram, Harish C. Pant, Antonio Cardone* and Jeffery B. Klauda*, ","doi":"10.1021/acs.biochem.4c00148","DOIUrl":null,"url":null,"abstract":"<p >Munc18–1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18–1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer’s disease (AD) pathological target. Experimental <i>in vivo</i> and <i>in vitro</i> studies suggest that Munc18–1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18–1 that could potentially affect the Munc18–1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18–1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18–1, define the corresponding pharmacophores, and provide guidance for the <i>in vitro</i> validation of our findings to improve therapeutic efficacy and safety of p5.</p>","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":null,"pages":null},"PeriodicalIF":2.9000,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Investigation of the Effect of Peptide p5 Targeting CDK5-p25 Hyperactivity on Munc18–1 (P67) Regulating Neuronal Exocytosis Using Molecular Simulations\",\"authors\":\"Tejaswi Tammareddy, Walid Keyrouz, Ram D. Sriram, Harish C. Pant, Antonio Cardone* and Jeffery B. Klauda*, \",\"doi\":\"10.1021/acs.biochem.4c00148\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Munc18–1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18–1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer’s disease (AD) pathological target. Experimental <i>in vivo</i> and <i>in vitro</i> studies suggest that Munc18–1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18–1 that could potentially affect the Munc18–1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18–1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18–1, define the corresponding pharmacophores, and provide guidance for the <i>in vitro</i> validation of our findings to improve therapeutic efficacy and safety of p5.</p>\",\"PeriodicalId\":28,\"journal\":{\"name\":\"Biochemistry Biochemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2024-07-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemistry Biochemistry\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.biochem.4c00148\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemistry Biochemistry","FirstCategoryId":"1","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.biochem.4c00148","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Investigation of the Effect of Peptide p5 Targeting CDK5-p25 Hyperactivity on Munc18–1 (P67) Regulating Neuronal Exocytosis Using Molecular Simulations
Munc18–1 is an SM (sec1/munc-like) family protein involved in vesicle fusion and neuronal exocytosis. Munc18–1 is known to regulate the exocytosis process by binding with closed- and open-state conformations of Syntaxin1, a protein belonging to the SNARE family established to be central to the exocytosis process. Our previous work studied peptide p5 as a promising drug candidate for CDK5-p25 complex, an Alzheimer’s disease (AD) pathological target. Experimental in vivo and in vitro studies suggest that Munc18–1 promotes p5 to selectively inhibit the CDK5-p25 complex without affecting the endogenous CDK5 activity, a characteristic of remarkable therapeutic implications. In this paper, we identify several binding modes of p5 with Munc18–1 that could potentially affect the Munc18–1 binding with SNARE proteins and lead to off-target effects on neuronal communication using molecular dynamics simulations. Recent studies indicate that disruption of Munc18–1 function not only disrupts neurotransmitter release but also results in neurodegeneration, exhibiting clinical resemblance to other neurodegenerative conditions such as AD, causing diagnostic and treatment challenges. We characterize such interactions between p5 and Munc18–1, define the corresponding pharmacophores, and provide guidance for the in vitro validation of our findings to improve therapeutic efficacy and safety of p5.
期刊介绍:
Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.