Archives of biochemistry and biophysics最新文献

PPARγ-mediated amelioration of lipid metabolism abnormality by kaempferol 山奈酚介导的 PPARγ 对脂质代谢异常的改善作用

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-13 DOI: 10.1016/j.abb.2024.110154

{"title":"PPARγ-mediated amelioration of lipid metabolism abnormality by kaempferol","authors":"","doi":"10.1016/j.abb.2024.110154","DOIUrl":"10.1016/j.abb.2024.110154","url":null,"abstract":"<div><p>Kaempferol can exert biological functions by regulating various signaling pathways. This study evaluated the ameliorative effect of kaempferol on lipid accumulation using oleic acid and palmitic acid-treated HepG2 cells and high-fat diet mice. <em>In vitro</em> oil red O staining showed that kaempferol treatment improved lipid accumulation (<em>p</em> < 0.001 for TG content and <em>p</em> < 0.05 for TC content). Immunofluorescence, Western blot analysis and RT-qPCR showed that kaempferol could promote nuclear translocation of PPARγ and reduce the expression of PPARγ, C/EBPβ, and SREBP-1c. Dietary intervention with kaempferol could reduce the lipid accumulation in hepatocytes and inflammatory cell infiltration, as well as attenuated serum levels of IL-6 and TNF-α in HFD-fed mice (<em>p</em> < 0.001 for IL-6 and <em>p</em> < 0.01 for TNF-α at kaempferol 60 mg/kg/d). Meanwhile, histopathological examination revealed that there was no substantial damage or distinct inflammation lesions in organs at the experimental dose, including the heart, lung, kidney, and spleen. The aforementioned research findings can serve as references for further preclinical investigations on the potential of kaempferol to mitigate lipid accumulation.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232844","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

Treatment with a combination of myricitrin and exercise alleviates myocardial infarction in rats via suppressing Nrf2/HO-1 antioxidant pathway

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-11 DOI: 10.1016/j.abb.2024.110153

{"title":"Treatment with a combination of myricitrin and exercise alleviates myocardial infarction in rats via suppressing Nrf2/HO-1 antioxidant pathway","authors":"","doi":"10.1016/j.abb.2024.110153","DOIUrl":"10.1016/j.abb.2024.110153","url":null,"abstract":"<div><p>Myocardial infarction (MI) is the primary source of death in cardiovascular diseases. Myricitrin (MYR) is a phenolic compound known for its antioxidant properties. This study aimed to investigate the impact of MYR alone or combined with exercise on a rat model of MI and its underlying mechanism. Sprague-Dawley rats were randomized into 5 groups: sham-operated (Sham), MI-sedentary (MI-Sed), MI-exercise (MI-Ex), MI-sedentary + MYR (MI-Sed-MYR) and MI-exercise + MYR (MI-Ex-MYR). MI was induced through ligation of left anterior descending coronary artery. The treatment with exercise or MYR (30 mg/kg/d) gavage began one week after surgery, either individually or in combination. After 8 weeks, the rats were assessed for cardiac function. Myocardial injuries were estimated using triphenyltetrazolium chloride, sirius red and Masson staining. Changes in reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔΨm), apoptosis and Nrf2/HO-1 pathway were analyzed by ROS kit, JC-1 kit, TUNEL assay, Western blot and immunohistochemistry. Both MYR and exercise treatments improved cardiac function, reduced infarct size, suppressed collagen deposition, and decreased myocardial fibrosis. Additionally, both MYR and exercise treatments lowered ROS production induced by MI, restored ΔΨm, and attenuated oxidative stress and apoptosis in cardiomyocytes. Importantly, the combination of MYR and exercise showed greater efficacy compared to individual treatments. Mechanistically, the combined intervention activated the Nrf2/HO-1 signaling pathway. These findings suggest that the synergistic effect of MYR and exercise may offer a promising therapeutic approach for alleviating MI.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242090","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

STC2 knockdown inhibits cell proliferation and glycolysis in hepatocellular carcinoma through promoting autophagy by PI3K/Akt/mTOR pathway

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-11 DOI: 10.1016/j.abb.2024.110149

{"title":"STC2 knockdown inhibits cell proliferation and glycolysis in hepatocellular carcinoma through promoting autophagy by PI3K/Akt/mTOR pathway","authors":"","doi":"10.1016/j.abb.2024.110149","DOIUrl":"10.1016/j.abb.2024.110149","url":null,"abstract":"<div><h3>Background</h3><p>The pathogenesis exploration and timely intervention of hepatocellular carcinoma (HCC) are crucial due to its global impact on human health. As a general tumor biomarker, stanniocalcin 2 (STC2), its role in HCC remains unclear. We aimed to analyze the effect and mechanism of STC2 on HCC.</p></div><div><h3>Methods</h3><p>STC2 expressions in HCC tissues and cell lines were measured. si-STC2 and oe-STC2 transfections were utilized to analyze how STC2 affected cell functions. Functional enrichment analysis of STC2 was performed by Gene Set Enrichment Analysis (GSEA). The regulatory mechanism of STC2 on HCC was investigated using 2-DG, 3-MA, IGF-1, Rap, and LY294002. The impact of STC2 on HCC progression <em>in vivo</em> was evaluated by the tumor formation experiment.</p></div><div><h3>Results</h3><p>Higher levels of STC2 expression were observed in HCC tissues and cell lines. Besides, STC2 knockdown reduced proliferation, migration, and invasion, while inducing cell apoptosis. Further analysis indicated a positive correlation between STC2 and glycolysis. STC2 knockdown inhibited glycolysis progression and down-regulated the expressions of PKM2, GLUT1, and HK2 in HCC cells. However, treatment with glycolysis inhibitor (2-DG) prevented oe-STC2 from promoting the growth of HCC cells. Additionally, STC2 knockdown up-regulated the levels of LC3II/LC3I and Beclin1 and reduced the phosphorylation of PI3K, AKT, and mTOR. Treatment with 3-MA, IGF-1, Rap, and LY294002 altered the function of STC2 on proliferation and glycolysis in HCC cells. Tumor formation experiment results revealed that STC2 knockdown inhibited HCC progression.</p></div><div><h3>Conclusions</h3><p>STC2 knockdown inhibited cell proliferation and glycolysis in HCC through the PI3K/Akt/mTOR pathway-mediated autophagy induction.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242093","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

Exploration of lipid bilayer mechanical properties using molecular dynamics simulation

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-10 DOI: 10.1016/j.abb.2024.110151

{"title":"Exploration of lipid bilayer mechanical properties using molecular dynamics simulation","authors":"","doi":"10.1016/j.abb.2024.110151","DOIUrl":"10.1016/j.abb.2024.110151","url":null,"abstract":"<div><p>Important biological structures known for their exceptional mechanical qualities, lipid bilayers are essential to many cellular functions. Fluidity, elasticity, permeability, stiffness, tensile strength, compressibility, shear viscosity, line tension, and curvature elasticity are some of the fundamental characteristics affecting their behavior. The purpose of this review is to examine these characteristics in more detail by molecular dynamics simulation, elucidating their importance and the elements that lead to their appearance in lipid bilayers. Comprehending the mechanical characteristics of lipid bilayers is critical for creating medications, drug delivery systems, and biomaterials that interact with biological membranes because it allows one to understand how these materials respond to different stresses and deformations.</p><p>The influence of mechanical characteristics on important lipid bilayer properties is examined in this review. The mechanical properties of lipid bilayers were clarified through the use of molecular dynamics simulation analysis techniques, including bilayer thickness, stress-strain analysis, lipid bilayer area compressibility, membrane bending rigidity, and time- or ensemble-averaged the area per lipid evaluation. We explain the significance of molecular dynamics simulation analysis methods, providing important new information about the stability and dynamic behavior of the bilayer. In the end, we hope to use molecular dynamics simulation to provide a comprehensive understanding of the mechanical properties and behavior of lipid bilayers, laying the groundwork for further studies and applications. Taken together, careful investigation of these mechanical aspects deepens our understanding of the adaptive capacities and functional roles of lipid bilayers in biological environments.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242030","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

Understanding the stability and dynamics of influenza a H5N1 polymerase PB2 CAP-Binding domain in complex with natural compounds for antiviral drug discovery

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-10 DOI: 10.1016/j.abb.2024.110148

{"title":"Understanding the stability and dynamics of influenza a H5N1 polymerase PB2 CAP-Binding domain in complex with natural compounds for antiviral drug discovery","authors":"","doi":"10.1016/j.abb.2024.110148","DOIUrl":"10.1016/j.abb.2024.110148","url":null,"abstract":"<div><p>Influenza A virus, particularly the H5N1 strain, poses a significant threat to public health due to its ability to cause severe respiratory illness and its high mortality rate. Traditional antiviral drugs targeting influenza A virus have faced challenges such as drug resistance and limited efficacy. Therefore, new antiviral compounds are needed to be discovered and developed. This study concentrated on examining the stability and behavior of the H5N1 polymerase PB2 CAP-binding domain when interacting with natural compounds, aiming to identify potential candidates for antiviral drug discovery. Through the virtual screening process, four lead compounds, ZINC000096095464, ZINC000044404209, ZINC000001562130, and ZINC000059779788, were selected, and these compounds showed binding energies −9.6, −9.4, −9.3, and −9.2 kcal/mol, respectively. When complexed with PB2, the ligand showed acceptable binding stability due to significant bond formation. However, during the 200ns MD simulation analysis, three (ZINC000096095464, ZINC000044404209, and ZINC000059779788) showed significant stability, which was proven by the trajectory analysis. The Rg-RMSD-based FEL plot showed significant structural stability due to stable conformers. The free-binding energy calculation also validates the stability of these complexes. This study offers valuable insights into the stability and dynamics of the H5N1 polymerase PB2 CAP-binding domain in complexes with natural compounds. These findings highlight the potential of these natural compounds as antiviral agents against the H5N1 influenza virus. Furthermore, this research contributes to the broader field of influenza virus treatment by demonstrating the effectiveness of computational methods in predicting and evaluating the stability and dynamics of potential drug candidates.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242091","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

Unlocking the potential of signature-based drug repurposing for anticancer drug discovery 释放基于特征的药物再利用潜力，促进抗癌药物的发现

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-10 DOI: 10.1016/j.abb.2024.110150

{"title":"Unlocking the potential of signature-based drug repurposing for anticancer drug discovery","authors":"","doi":"10.1016/j.abb.2024.110150","DOIUrl":"10.1016/j.abb.2024.110150","url":null,"abstract":"<div><p>Cancer is the leading cause of death worldwide and is often associated with tumor relapse even after chemotherapeutics. This reveals malignancy is a complex process, and high-throughput omics strategies in recent years have contributed significantly in decoding the molecular mechanisms of these complex events in cancer. Further, the omics studies yield a large volume of cancer-specific molecular signatures that promote the discovery of cancer therapy drugs by a method termed signature-based drug repurposing. The drug repurposing method identifies new uses for approved drugs beyond their intended initial therapeutic use, and there are several approaches to it. In this review, we discuss signature-based drug repurposing in cancer, how cancer omics have revolutionized this method of drug discovery, and how one can use the cancer signature data for repurposed drug identification by providing a step-by-step procedural handout. This modern approach maximizes the use of existing therapeutic agents for cancer therapy or combination therapy to overcome chemotherapeutics resistance, making it a pragmatic and efficient alternative to traditional resource-intensive and time-consuming methods.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167772","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

Concurrent detection of the mitochondrial DNA copy number and the +35G/C polymorphism in the mitochondrial transcription factor A gene in endometriosis

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-10 DOI: 10.1016/j.abb.2024.110152

{"title":"Concurrent detection of the mitochondrial DNA copy number and the +35G/C polymorphism in the mitochondrial transcription factor A gene in endometriosis","authors":"","doi":"10.1016/j.abb.2024.110152","DOIUrl":"10.1016/j.abb.2024.110152","url":null,"abstract":"<div><h3>Background and aim</h3><p>Endometriosis is a chronic gynecological inflammatory disease. The mitochondrial DNA copy number (mtDNA CN) and mitochondrial transcription factor A (TFAM) are known to contribute to human pathologies and cancer. Therefore, this study aims to reveal the association of mtDNA CN and TFAM+35G/C (rs1937) polymorphism with the risk of endometriosis in Egyptian females.</p></div><div><h3>Materials and methods</h3><p>This case-control study involved 160 Egyptian females divided into two groups: 80 endometriosis cases and 80 controls. The mtDNA CN was quantified using a real-time quantitative PCR (qPCR), and the TFAM +35G/C SNP (rs1937) was genotyped using the TaqMan allelic discrimination assay technique.</p></div><div><h3>Results</h3><p>The mtDNA CN was markedly decreased in endometriosis cases compared to controls (P < 0. 001). TFAM rs1937 genotypes and allele distributions were all in Hardy-Weinberg equilibrium. The GC genotype and the ‘C’ allele frequency (P = 0.015 and P = 0.017, respectively) were substantially greater in endometriosis cases.</p></div><div><h3>Conclusion</h3><p>Decreased mtDNA CN and the GC genotype of TFAM +35G/C polymorphism were significantly associated with the risk of endometriosis in Egyptian females.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242092","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

Mechanisms of doxorubicin-induced cardiac inflammation and fibrosis; therapeutic targets and approaches. 多柔比星诱发心脏炎症和纤维化的机制；治疗目标和方法。

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-05 DOI: 10.1016/j.abb.2024.110140

Linghua Song, Qingzhuo Qiu, Fei Ju, Chunyan Zheng

{"title":"Mechanisms of doxorubicin-induced cardiac inflammation and fibrosis; therapeutic targets and approaches.","authors":"Linghua Song, Qingzhuo Qiu, Fei Ju, Chunyan Zheng","doi":"10.1016/j.abb.2024.110140","DOIUrl":"https://doi.org/10.1016/j.abb.2024.110140","url":null,"abstract":"<p><p>Doxorubicin plays a pivotal role in the treatment of various malignancies. Despite its efficacy, the cardiotoxicity associated with doxorubicin limits its clinical utility. The cardiotoxic nature of doxorubicin is attributed to several mechanisms, including its interference with mitochondrial function, the generation of reactive oxygen species (ROS), and the subsequent damage to cardiomyocyte DNA, proteins, and lipids. Furthermore, doxorubicin disrupts the homeostasis of cardiac-specific transcription factors and signaling pathways, exacerbating cardiac dysfunction. Oxidative stress, cell death, and other severe changes, such as mitochondrial dysfunction, activation of pro-oxidant enzymes, the renin-angiotensin system (RAS), endoplasmic reticulum (ER) stress, and infiltration of immune cells in the heart after treatment with doxorubicin, may cause inflammatory and fibrotic responses. Fibrosis and inflammation can lead to a range of disorders in the heart, resulting in potential cardiac dysfunction and disease. Various adjuvants have shown potential in preclinical studies to mitigate these challenges associated with cardiac inflammation and fibrosis. Antioxidants, plant-based products, specific inhibitors, and cardioprotective drugs may be recommended to alleviate cardiotoxicity. This review explores the complex mechanisms of doxorubicin-induced heart inflammation and fibrosis, identifies possible cellular and molecular targets, and investigates potential substances that could help reduce these harmful effects.</p>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144902","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

RNF113A as a poor prognostic factor promotes metastasis and invasion of cervical cancer through miR197/PRP19/P38MAPK signaling pathway 通过 miR197/PRP19/P38MAPK 信号通路促进宫颈癌转移和侵袭的不良预后因子 RNF113A

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-09-04 DOI: 10.1016/j.abb.2024.110139

{"title":"RNF113A as a poor prognostic factor promotes metastasis and invasion of cervical cancer through miR197/PRP19/P38MAPK signaling pathway","authors":"","doi":"10.1016/j.abb.2024.110139","DOIUrl":"10.1016/j.abb.2024.110139","url":null,"abstract":"<div><p>It has been discovered that aberrant expression of RNF113A plays a significant role in various diseases, including esophageal cancer, hepatocellular carcinoma, and X-linked trichothiodystrophy syndrome. Nevertheless, its functional implications in cervical cancer (CC) remain unclear. The objective of this study was to investigate the role of RNF113A in both the development and prognosis of CC. To achieve this objective, a total of sixty cases were included in the follow-up investigation. The findings revealed a significant up-regulation of RNF113A protein in CC tissues compared to paired paracancerous tissues, and a high expression level of RNF113A was strongly associated with malignant phenotypes such as lymph node metastasis, differentiation degree, depth of invasion, and FIGO stage. Meanwhile, RNF113A was found to be an independent prognostic risk factor, with its high expression significantly correlating with a reduced overall survival period in patients. To elucidate the underlying cause and mechanism of the unfavorable prognosis associated with RNF113A, comprehensive functional investigations were conducted both <em>in vitro</em> and <em>in vivo</em>.Interestingly, it was revealed that RNF113A promoted migration and invasion while inhibiting apoptosis of CC cells, thereby contributing to a poor prognosis. Mechanistically, RNF113A regulated the progression and prognosis of CC through the miR197/Prp19/p38Mark signaling pathway. Overall, our findings underscore the potential clinical significance of RNF113A as an unfavorable prognostic factor in CC.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0003986124002613/pdfft?md5=efaed75df28e315c5a6aef68ce44ea50&pid=1-s2.0-S0003986124002613-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insight of the molecular mechanism of inhibitors located at different allosteric sites regulating the activity of wild type and mutant KRAS (G12) 揭示位于不同异构位点的抑制剂调节野生型和突变型 KRAS (G12) 活性的分子机制。

IF 3.8 3区生物学

Archives of biochemistry and biophysics Pub Date : 2024-08-30 DOI: 10.1016/j.abb.2024.110137

{"title":"Insight of the molecular mechanism of inhibitors located at different allosteric sites regulating the activity of wild type and mutant KRAS (G12)","authors":"","doi":"10.1016/j.abb.2024.110137","DOIUrl":"10.1016/j.abb.2024.110137","url":null,"abstract":"<div><p>As the important hub of many cellular signaling networks, KRAS (Kirsten rat sarcoma viral oncogene homologue) has been identified as a tumor biomarker. It is the frequently mutated oncogene in human cancers, and KRAS protein activation caused by mutations, such as G12D, has been found in many human tumors tissues. Although, there are two specific allosteric sites (AS1 and AS2) on the KRAS protein that can be used as the targets for inhibitor development, the difference of regulatory mechanisms between two individual allosteric sites still not be reported. Here, using molecular dynamics simulations combined with molecular mechanics generalized born surface area (MM/GBSA) analysis, we found that both of the inhibitors, located at AS1 and AS2, were able to reduce the binding free energy between wild type, mutant KRAS (G12/D/V/S/C) and GTP remarkably, however the effect of inhibitors on the binding free energy between wild type, mutant KRAS and GDP was limited. In addition, the degree of decrease of binding free energy between KRAS and GTP caused by inhibitors at AS2 was significantly greater than that caused by inhibitors at AS1. Further analysis revealed that both inhibitors at AS1 and AS2 were able to regulate the fluctuation of Switch Ⅰ and Switch Ⅱ to expand the pocket of the orthosteric site (GTP binding site), thereby reducing the binding of KRAS to GTP. Noteworthy there was significant differences in the regulatory preferences on Switch Ⅰ and Switch Ⅱ between two type inhibitor. The inhibitor at AS2 mainly regulated Switch Ⅱ to affect the pocket of the orthosteric site, while the inhibitor at AS1 mainly expand the pocket of the orthosteric site by regulating the fluctuation of Switch Ⅰ. Our study compared the differences between two type inhibitors in regulating the KRAS protein activity and revealed the advantages of the AS2 as the small molecule drug target, aiming to provide theoretical guidance for the research of novel KRAS protein inhibitors.</p></div>","PeriodicalId":8174,"journal":{"name":"Archives of biochemistry and biophysics","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103783","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