Journal of Biomolecular Structure & Dynamics最新文献_第7页

HrpY protein of Ralstonia solanacearum exhibits spontaneous formation of pilus like assembly: analysis of its stability. Ralstonia solanacearum 的 HrpY 蛋白自发形成类似柔毛的组装：稳定性分析。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-06-01 Epub Date: 2024-01-17 DOI: 10.1080/07391102.2024.2304678

Naveen Arasakumar, Vikraam Loganathan, Ramanathan Natesh, Karthe Ponnuraj

{"title":"HrpY protein of Ralstonia solanacearum exhibits spontaneous formation of pilus like assembly: analysis of its stability.","authors":"Naveen Arasakumar, Vikraam Loganathan, Ramanathan Natesh, Karthe Ponnuraj","doi":"10.1080/07391102.2024.2304678","DOIUrl":"10.1080/07391102.2024.2304678","url":null,"abstract":"Type 3 secretory system (T3SS), a complex protein machinery has a unique virulence mechanism that involves injecting effector proteins directly into host cells. The T3SS effector proteins are transported through an extracellular long hollow needle made up of multiple copies of a small protein. In T3SS of the plant pathogen Ralstonia solanacearum, the 8.6 kDa HrpY protein assembles into a large needle like apparatus (pilus) for transporting effector proteins. To study structural details of HrpY, we recombinantly expressed and purified HrpY in E. coli. The dynamic light scattering (DLS) analysis showed that rHrpY has spontaneously formed oligomers of large order (>100 nm). Transmission electron microscopy of rHrpY samples revealed that the large structures are tube like assembly having dimensions 86.3-166.6 nm and 5.8-6.8 nm in length and width respectively. Different molecular sizes of the purified rHrpY hindered the crystallization of the protein. The stability of oligomer assembly was studied with denaturants and surfactants. Denaturants like urea and guanidine HCl could not break them apart; however, detergents like SDS, sarkosyl, Octyl-β-Glucoside, CHAPS, Tween 20, Tween 80 and Triton X-100 showed disassembly of the oligomer. rHrpY assembly was found to withstand up to 50 °C and the circular dichroism analysis revealed that there is no significant change in the secondary structural composition with increase in temperature. However, change in the secondary structure was observed with the addition of SDS.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"4591-4602"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478605","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

Unveiling the potential of recently FDA-approved drugs as quorum sensing inhibitors against P. Aeruginosa using high-performance computational techniques. 利用高性能计算技术，揭示最近获得 FDA 批准的药物作为法定人数感应抑制剂抗击绿脓杆菌的潜力。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-06-01 Epub Date: 2024-01-17 DOI: 10.1080/07391102.2024.2304682

Debanjan Dey, Anoop Kumar

{"title":"Unveiling the potential of recently FDA-approved drugs as quorum sensing inhibitors against P. Aeruginosa using high-performance computational techniques.","authors":"Debanjan Dey, Anoop Kumar","doi":"10.1080/07391102.2024.2304682","DOIUrl":"10.1080/07391102.2024.2304682","url":null,"abstract":"Through cell-to-cell communication, activation of efflux pumps, formation of biofilms, and other mechanisms, pseudomonas aeruginosa's quorum sensing systems (QSS), notably the lasl/las-r system, contribute a vital role in the development of anti-microbial resistance (AMR). Identifying potential drugs against these targets could have significant implications for combating pseudomonal infections. The current study aims to identify promising recently FDA-approved drugs against lasl/las-r proteins. The ligands were selected from the FDA-approved drug lists of the last 5 years. Out of 202, 78 drugs were checked for interaction with lasl/las-r protein and 4 drugs revealed top binding conformations characterized by favorable energetic profiles within the active site of the las-r protein which were further assigned for 250-ns molecular dynamics (MD) simulation. The MD analysis confirmed the dynamical stability of brexanolone and oteseconazole with las-r protein. The root mean square deviation (RMSD), radius of gyration (Rg) and solvent-accessible surface area (SASA) analysis have indicated less deviation, more compactness of protein and less exposure of protein ligand complex to its surroundings as compared to the reference ligand-protein complex. The hydroxyl group in the oteseconazole whereas hydroxyl and ketone group in the brexanolone were responsible for hydrogen bonds with the active site residue of las r ptotein as indicated by ligand-protein contacts diagram. The binding energies per residue analysis revealed TYR-47 as the most contributing amino acid residue for interaction with oteseconazole and brexanolone. The identified drugs may be potential repurposing candidates against pseudomonal infections through inhibition of las-r protein.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"4698-4715"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478614","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

Identification of amentoflavone as a potent SARS-CoV-2 M^pro inhibitor: a combination of computational studies and in vitro biological evaluation. 鉴定作为 SARS-CoV-2 Mpro 有效抑制剂的门黄酮：计算研究与体外生物评估的结合。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-06-01 Epub Date: 2024-01-23 DOI: 10.1080/07391102.2024.2304676

Prabuddha Bhattacharya, Anirban Mandal

{"title":"Identification of amentoflavone as a potent SARS-CoV-2 Mpro inhibitor: a combination of computational studies and in vitro biological evaluation.","authors":"Prabuddha Bhattacharya, Anirban Mandal","doi":"10.1080/07391102.2024.2304676","DOIUrl":"10.1080/07391102.2024.2304676","url":null,"abstract":"Small-molecule inhibitors of SARS-CoV-2 Mpro that block the active site pocket of the viral main protease have been considered potential therapeutics for the development of drugs against SARS-CoV-2. Here, we report the identification of amentoflavone (a biflavonoid) through docking-based virtual screening of a library comprised of 231 compounds consisting of flavonoids and isoflavonoids. The docking results were further substantiated through extensive analysis of the data obtained from all-atom 150 ns MD simulation. End-state effective free energy calculations using MM-PBSA calculations further suggested that (Ra)-amentoflavone (C3'-C8''-atropisomer) may show a greater binding affinity towards the Mpro than (Sa)-amentoflavone. In vitro cytotoxicity assay established that amentoflavone showed a high CC50 value indicating much lower toxicity. Further, potent inhibition of the Mpro by amentoflavone was established by studying the effect on HEK293T cells treated with SARS-CoV-2 Mpro expressing plasmid.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"4659-4677"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139540816","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

C-30 analogues of betulinic acid as potent cytotoxic agents: design, synthesis, biological evaluation and in-silico studies. 作为强效细胞毒剂的白桦脂酸 C-30 类似物：设计、合成、生物学评价和微观研究。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-06-01 Epub Date: 2024-02-29 DOI: 10.1080/07391102.2024.2303612

Santosh K Rath, Rakesh K Nagar, Sanjib Das, Govind Yadav, Debaraj Mukherjee, Buddh Singh, Samar Singh, Payare L Sangwan

引用次数: 0

Targeting Mycobacterium tuberculosis: identification of potential phytochemicals from traditional plants against glucosyl-3-phosphoglycerate phosphatase (GpgP). 靶向结核分枝杆菌：从传统植物中鉴定抗葡萄糖-3-磷酸甘油酸磷酸酶（GpgP）的潜在植物化学物质。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-31 DOI: 10.1080/07391102.2025.2509789

Pratyaksha Singh, Saurabh Kumar Bhati, Monika Jain, Rashmi Prabha Singh, Jayaraman Muthukumaran, Amit Kumar Singh

{"title":"Targeting Mycobacterium tuberculosis: identification of potential phytochemicals from traditional plants against glucosyl-3-phosphoglycerate phosphatase (GpgP).","authors":"Pratyaksha Singh, Saurabh Kumar Bhati, Monika Jain, Rashmi Prabha Singh, Jayaraman Muthukumaran, Amit Kumar Singh","doi":"10.1080/07391102.2025.2509789","DOIUrl":"https://doi.org/10.1080/07391102.2025.2509789","url":null,"abstract":"Tuberculosis (TB) is a transmissible disease that causes severe infections in adults as well as in infants, as they have immature immune systems. Lungs are the main site for pulmonary TB infection, although TB can affect other parts like lymph nodes, bone, joints, etc., which is known as extrapulmonary TB. M. tuberculosis is becoming one of the world's most severe pathogens due to growing multidrug resistance (MDR) and extensively drug resistance (XDR), rendering treatment medications useless. GpgP was chosen as the promising drug target protein in this study because it is primarily involved in the catalysis of the second step in the production of Methylglucose lipopolysaccharides (MGLPs), which regulate the synthesis of mycolic acids, which are an essential component for building the mycobacterial cell envelope. The cell envelope of M. tuberculosis is unique and is responsible for the bacteria's flexibility and pathogenicity. An in-house library of phytochemicals was utilized for screening in AutoDock Vina, and then the ligands were docked using AutoDock with the drug target protein for further validation. Then, four ligands were filtered out using SwissADME that were further studied by performing molecular dynamic simulations. After a thorough analysis, CID_446611 and CID_5282146 ligands were identified as potential inhibitors of GpgP.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-9"},"PeriodicalIF":2.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191859","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

DeepCR: predicting cytokine receptor proteins through pretrained language models and deep learning networks. DeepCR：通过预训练语言模型和深度学习网络预测细胞因子受体蛋白。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-31 DOI: 10.1080/07391102.2025.2512448

Van The Le, Juan Peter Timothy Yuune, Thi Thu Phuong Vu, Muhammad Shahid Malik, Yu-Yen Ou

{"title":"DeepCR: predicting cytokine receptor proteins through pretrained language models and deep learning networks.","authors":"Van The Le, Juan Peter Timothy Yuune, Thi Thu Phuong Vu, Muhammad Shahid Malik, Yu-Yen Ou","doi":"10.1080/07391102.2025.2512448","DOIUrl":"https://doi.org/10.1080/07391102.2025.2512448","url":null,"abstract":"Cytokine receptors play a pivotal role in mediating the immune response and are critical in cytokine storms, which underlie the pathogenesis of conditions such as acute respiratory distress syndrome (ARDS) and autoimmune disorders. Identifying cytokine receptors is essential for understanding their biological functions, exploring therapeutic targets, and guiding clinical interventions. Traditional biochemical methods to identify cytokine receptors are labor-intensive, costly, and time-consuming, prompting the need for more efficient alternatives. Recent advances in computational biology have enabled the use of machine learning to classify cytokine receptor proteins. Most existing approaches focused on homologous features and protein composition to classify cytokine families, but no dedicated studies have been conducted on cytokine receptor proteins. This gap presents an opportunity to develop a method specifically for classifying cytokine receptors among other membrane proteins. In this study, we present a novel classification framework combining pre-trained language models (PLMs) with a multi-window convolutional neural network (mCNN) architecture for the fast and accurate identification of cytokine receptor proteins. PLMs, such as ProtTrans and ESM variants, capture biochemical context directly from raw protein sequences, while mCNN efficiently extracts local and global sequence patterns using convolutional layers with varying window sizes. Our model achieved an AUC of 0.96 in the training as well as 0.97 and 0.93 in two independent tests, demonstrating its effectiveness in distinguishing cytokine receptors from non-cytokine receptor proteins. By eliminating the need for manual feature extraction, this approach offers a robust and scalable solution for protein classification, paving the way for its application in drug discovery and understanding cytokine-mediated diseases.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191858","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

Integrated in-silico approach to explore the therapeutic potential of RNAs and druggable polyphenols to mine alternative breast cancer therapeutic strategies targeting cancer hallmarks. 集成硅方法探索rna和可药物多酚的治疗潜力，以挖掘针对癌症特征的替代乳腺癌治疗策略。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-30 DOI: 10.1080/07391102.2025.2497465

Sohini Chakraborty, Satarupa Banerjee

{"title":"Integrated in-silico approach to explore the therapeutic potential of RNAs and druggable polyphenols to mine alternative breast cancer therapeutic strategies targeting cancer hallmarks.","authors":"Sohini Chakraborty, Satarupa Banerjee","doi":"10.1080/07391102.2025.2497465","DOIUrl":"https://doi.org/10.1080/07391102.2025.2497465","url":null,"abstract":"Breast cancer (BC) is a global disease. A polyphenol-based therapeutic strategy is utilised to discover novel biotargets for breast cancer by assessing their drug-likeliness and toxicity. 1067 mRNAs associated with the ten initial hallmarks are retrieved from a publicly available database. However, no interacting mRNA data were found for two of the new hallmarks. The mRNAs are compared with the GEPIA database data to obtain the final 15 differentially expressed genes (DEGs) for the hallmarks. The interacting miRNAs of the DEGs are retrieved from a publicly available database. 56 druggable polyphenols are finalised for the study owing to their drug-likeliness and toxicity. Finally, a comprehensive interaction network-based analysis was carried out for the DEGs-interacting miRNAs and common druggable polyphenols. This revealed daidzein (DAI), resveratrol and 6-Gingerol; miR-663, miR-148a, miR328 and miR27b; BIRC5, CCNA2, EGFR, STAT5B and CDKN2A as significant polyphenols, miRNAs and mRNAs, respectively. Subsequently, a two-step docking approach along with molecular dynamics simulation (MDS) was also used to assess the therapeutic potential of the three polyphenols. Molecular docking revealed DAI-CCNA2 as the best fit among all the test complexes. For MDS, DAI-CCNA2 was simulated in comparison with CCNA2-Olaparib (OLA), an approved drug for breast cancer. MDS results verified DAI (the proposed drug) to be a potential candidate to combat breast cancer. Identification of druggable polyphenols using such a comprehensive in-silico approach can aid in providing a novel therapeutic strategy to combat the drawbacks associated with conventional therapies that can be further validated in an experimental setup.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183575","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

Biochanin A, an isoflavone isolated from Dalbergia sissoo Roxb. ex DC., leaves promote ROS-mediated and caspase-dependent apoptosis in lung adenocarcinoma cells. 从黄檀中分离得到的生物茶素A异黄酮。交货。，叶片促进ros介导的和caspase依赖的肺腺癌细胞凋亡。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-27 DOI: 10.1080/07391102.2025.2507820

Anjali B Thakkar, Ramalingam B Subramanian, Vasudev R Thakkar, Sampark S Thakkar, Jignesh Prajapati, Dweipayan Goswami, Parth Thakor

{"title":"Biochanin A, an isoflavone isolated from Dalbergia sissoo Roxb. ex DC., leaves promote ROS-mediated and caspase-dependent apoptosis in lung adenocarcinoma cells.","authors":"Anjali B Thakkar, Ramalingam B Subramanian, Vasudev R Thakkar, Sampark S Thakkar, Jignesh Prajapati, Dweipayan Goswami, Parth Thakor","doi":"10.1080/07391102.2025.2507820","DOIUrl":"10.1080/07391102.2025.2507820","url":null,"abstract":"The objective of this study was to isolate and characterize a cytotoxic compound from the hydromethanolic extract of Dalbergia sissoo Roxb. ex DC. leaves using the cold percolation technique. Thin-layer chromatography was employed to isolate the cytotoxic component from the crude plant extract, and its cytotoxicity against lung adenocarcinoma (A549) cells was evaluated using the MTT assay. The structure of the isolated cytotoxic compound was determined through FTIR, NMR, UV analysis, and LC-MS/MS methods. Through comprehensive characterization, a cytotoxic compound called Biochanin A (BA) was identified, exhibiting significant anticancer activity with an IC50 value of 21.92 ± 2.19 μM against A549 cells, while demonstrating lower cytotoxicity towards normal lung cells (WI-38) with an IC50 value of 285.12 ± 2.19 μM. Notably, BA induced morphological changes in A549 cells, leading to apoptotic alterations and the generation of reactive oxygen species (ROS), as confirmed by multiple techniques (AO/EB, DAPI, Giemsa). In silico molecular docking, ADMET, MMGBSA, and molecular dynamics simulation investigations support the RT-PCR and cell biology findings. As a result, BA's molecular mechanism of action involves ROS-induced apoptosis mediated by caspases 9 and 3.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-25"},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159314","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

Investigating the mechanism of corilagin interfering with HSV-2 replication: an in vitro and in silico analysis of the cGAS-STING pathway. 研究胶原蛋白干扰HSV-2复制的机制：cGAS-STING途径的体外和计算机分析。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-27 DOI: 10.1080/07391102.2025.2508347

Hao Zhang, Liang Cheng, Xueshi Zhou, Renfang Chen, Feng Ju, Qigang Dong

{"title":"Investigating the mechanism of corilagin interfering with HSV-2 replication: an in vitro and in silico analysis of the cGAS-STING pathway.","authors":"Hao Zhang, Liang Cheng, Xueshi Zhou, Renfang Chen, Feng Ju, Qigang Dong","doi":"10.1080/07391102.2025.2508347","DOIUrl":"https://doi.org/10.1080/07391102.2025.2508347","url":null,"abstract":"Herpes simplex virus type 2 (HSV-2) represents a significant etiological agent of recurrent and symptomatic genital herpes, which poses considerable risks to public health and the global economy. The cGAS (cyclic GMP-AMP synthase) protein, a pivotal component in the cGAS/STING DNA-sensing pathway, is an appealing target for pharmacological intervention due to its essential function in the immune response against DNA viruses. Recent investigations have indicated that corilagin, a polyphenolic compound derived from plants, exhibits a wide range of antiviral properties. In this study, we utilized molecular docking, molecular dynamics simulations, MM-PBSA analysis and in vitro experiments to explore the binding sites and interaction dynamics of corilagin with the cGAS protein. Our findings illustrated that corilagin formed a greater number of intramolecular hydrogen bonds with the cGAS protein and displayed lower binding energy relative to the original ligand found in the Protein Data Bank (PDB), thereby suggesting its enhanced potency. In vitro assays confirmed that corilagin effectively mitigated the overactivation of the cGAS-STING pathway, alleviated inflammation and inhibited apoptosis in HaCaT cells, thereby demonstrating a therapeutic potential against HSV-2 infection. In summary, corilagin may act as a structural template for further modifications aimed at developing more effective cGAS inhibitors, thereby advancing the treatment of viral infectious diseases.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-14"},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159317","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

Exploring the allosteric effect of SHP2 Tyr62 phosphorylation on the emergence of acquired resistance to allosteric inhibitor SHP099. 探讨SHP2 Tyr62磷酸化对抗变构抑制剂SHP099获得性耐药产生的变构作用。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-05-27 DOI: 10.1080/07391102.2025.2507815

Tingting Du, Lei Gu, Shenqian Xu, Jingfeng Zhang, Xiaoou Qiu, Wuxia Liu, Guodong Zheng, Bei Li, Bin Zhou, Minyu Li

{"title":"Exploring the allosteric effect of SHP2 Tyr62 phosphorylation on the emergence of acquired resistance to allosteric inhibitor SHP099.","authors":"Tingting Du, Lei Gu, Shenqian Xu, Jingfeng Zhang, Xiaoou Qiu, Wuxia Liu, Guodong Zheng, Bei Li, Bin Zhou, Minyu Li","doi":"10.1080/07391102.2025.2507815","DOIUrl":"https://doi.org/10.1080/07391102.2025.2507815","url":null,"abstract":"The Src homology-2 (SH2)-containing phosphatase 2 (SHP2), a non-receptor protein tyrosine phosphatase, is a key regulator modulating various signaling pathways. Recent studies have revealed that phosphorylation of Tyr62 (pY62) on the N-SH2 domain of SHP2 causes the emergence of acquired resistance to the allosteric inhibitor of SHP2 (SHP099) that occupies the PTP catalytic domain. However, the allosteric mechanism underlying the insensitivity of the allosteric inhibitor SHP099 to the phosphorylated SHP2 (pSHP2) remains unexplored. In this study, multiple replica molecular dynamics (MD) simulations and the post-trajectory analyses (principal component analysis, dynamics cross-correlation matrix analysis, allosteric community analysis, and binding free energy calculations) were performed for the SHP2, pSHP2, SHP2-SHP099, and pSHP2-SHP099 complexes. MD results showed that SHP099 binding contributed to stabilize SHP2, but pY62 had a detrimental role in the stability of the pSHP2-SHP099 complex. Domain correlation analysis showed that pY62 increased the anti-correlated motions between the C-SH2 and N-SH2/PTP domains. Binding free energy calculations revealed that the protein-ligand interactions in the SHP2 - SHP099 complex were stronger than that of the pSHP2 - SHP099 complex. Further, Thr108, Phe113, and Glu250 might be the critical residues responsible for the loss of the binding affinity in the pSHP2 - SHP099 complex through a per-residue decomposition analysis and H-bond occupancy time analysis. Overall, this study may provide a mechanistic insight into the mechanism how the allosteric effect of pY62 of SHP2 on SHP099 binding.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-11"},"PeriodicalIF":2.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159315","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