Current Research in Structural Biology最新文献

{"title":"Computational identification of candidate inhibitors for Dihydrofolate reductase in Acinetobacter baumannii","authors":"Saurabh Kumar Bhati,&nbsp;Monika Jain,&nbsp;Jayaraman Muthukumaran,&nbsp;Amit Kumar Singh","doi":"10.1016/j.crstbi.2024.100127","DOIUrl":"10.1016/j.crstbi.2024.100127","url":null,"abstract":"<div><p><em>Acinetobacter baumannii</em> is one of the emerging causes of hospital acquired infections and this bacterium, due to multi-drug resistant and Extensive Drug resistant has been able to develop resistance against the antimicrobial agents that are being used to eliminate it. <em>A.baumannii</em> has been the cause of death in immune compromised patients in hospitals. Hence it is the urgent need of time to find potential inhibitors for this bacterium to cease its virulence and affect its survival inside host organisms. The Dihydrofolate reductase enzyme, which is an important biocatalyst in the conversion of Dihydrofolate to Tetrahydrofolate, is an important drug target protein. In the present study high throughput screening is used to identify the inhibitors of this enzyme. The prioritized ligand molecular candidates identified through virtual screening for the substrate binding site of the predicted model are Z1447621107, Z2604448220 and Z1830442365. The Molecular Dynamics Simulation study suggests that potential inhibitor of the Dihydrofolate reductase enzyme would prevent bacteria from completing its life cycle, affecting its survival. Finally the complexes were analysed for binding free energy of the Dihydrofolate reductase enzyme complexes with the ligands.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100127"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000047/pdfft?md5=f83d409176a71f1deed39eeb70ffa0bd&pid=1-s2.0-S2665928X24000047-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139635556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The active site of the SGNH hydrolase-like fold proteins: Nucleophile–oxyanion (Nuc-Oxy) and Acid–Base zones","authors":"Konstantin Denessiouk ,&nbsp;Alexander I. Denesyuk ,&nbsp;Sergei E. Permyakov ,&nbsp;Eugene A. Permyakov ,&nbsp;Mark S. Johnson ,&nbsp;Vladimir N. Uversky","doi":"10.1016/j.crstbi.2023.100123","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100123","url":null,"abstract":"<div><p>SGNH hydrolase-like fold proteins are serine proteases with the default Asp-His-Ser catalytic triad. Here, we show that these proteins share two unique conserved structural organizations around the active site: (1) the Nuc-Oxy Zone around the catalytic nucleophile and the oxyanion hole, and (2) the Acid-Base Zone around the catalytic acid and base. The Nuc-Oxy Zone consists of 14 amino acids cross-linked with eight conserved intra- and inter-block hydrogen bonds. The Acid–Base Zone is constructed from a single fragment of the polypeptide chain, which incorporates both the catalytic acid and base, and whose N- and C-terminal residues are linked together by a conserved hydrogen bond. The Nuc-Oxy and Acid-Base Zones are connected by an SHLink, a two-bond conserved interaction from amino acids, adjacent to the catalytic nucleophile and base.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100123"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000296/pdfft?md5=82ef7ca038a6e502846afff04ea64b3c&pid=1-s2.0-S2665928X23000296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139107209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery","authors":"Vandana Mishra ,&nbsp;Anuradha Deshmukh ,&nbsp;Ishan Rathore ,&nbsp;Satadru Chakraborty ,&nbsp;Swati Patankar ,&nbsp;Alla Gustchina ,&nbsp;Alexander Wlodawer ,&nbsp;Rickey Y. Yada ,&nbsp;Prasenjit Bhaumik","doi":"10.1016/j.crstbi.2024.100128","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100128","url":null,"abstract":"<div><p><em>Plasmodium</em> species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by <em>Plasmodium</em> parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating <em>Plasmodium</em> pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of <em>P. falciparum.</em> Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII <em>via</em> multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of <em>P. falciparum</em> PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100128"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000059/pdfft?md5=38e95df2fe38c0df8f4ac91d7d0249de&pid=1-s2.0-S2665928X24000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139505362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Living in trinity of extremes: Genomic and proteomic signatures of halophilic, thermophilic, and pH adaptation","authors":"Aidana Amangeldina ,&nbsp;Zhen Wah Tan ,&nbsp;Igor N. Berezovsky","doi":"10.1016/j.crstbi.2024.100129","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100129","url":null,"abstract":"<div><p>Since nucleic acids and proteins of unicellular prokaryotes are directly exposed to extreme environmental conditions, it is possible to explore the genomic-proteomic compositional determinants of molecular mechanisms of adaptation developed by them in response to harsh environmental conditions. Using a wealth of currently available complete genomes/proteomes we were able to explore signatures of adaptation to three environmental factors, pH, salinity, and temperature, observing major trends in compositions of their nucleic acids and proteins. We derived predictors of thermostability, halophilic, and pH adaptations and complemented them by the principal components analysis. We observed a clear difference between thermophilic and salinity/pH adaptations, whereas latter invoke seemingly overlapping mechanisms. The genome-proteome compositional trade-off reveals an intricate balance between the work of base paring and base stacking in stabilization of coding DNA and r/tRNAs, and, at the same time, universal requirements for the stability and foldability of proteins regardless of the nucleotide biases. Nevertheless, we still found hidden fingerprints of ancient evolutionary connections between the nucleotide and amino acid compositions indicating their emergence, mutual evolution, and adjustment. The evolutionary perspective on the adaptation mechanisms is further studied here by means of the comparative analysis of genomic/proteomic traits of archaeal and bacterial species. The overall picture of genomic/proteomic signals of adaptation obtained here provides a foundation for future engineering and design of functional biomolecules resistant to harsh environments.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100129"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000060/pdfft?md5=6db45050bbde9f78ac6d75eb6e876f66&pid=1-s2.0-S2665928X24000060-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139674781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guide to serial synchrotron crystallography","authors":"Ki Hyun Nam","doi":"10.1016/j.crstbi.2024.100131","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100131","url":null,"abstract":"<div><p>Serial crystallography (SX) is an emerging technique that can be used to determine the noncryogenic crystal structure of macromolecules while minimizing radiation damage. Applying SX using pump-probe or mix-and-inject techniques enables the observation of time-resolved molecular reactions and dynamics in macromolecules. After the successful demonstration of the SX experimental technique with structure determination in serial femtosecond crystallography using an X-ray free electron laser, this method was adapted to the synchrotron, leading to the development of serial synchrotron crystallography (SSX). SSX offers new opportunities for researchers to leverage SX techniques, contributing to the advancement of structural biology and offering a deeper understanding of the structure and function of macromolecules. This review covers the background and advantages of SSX and its experimental approach. It also discusses important considerations when conducting SSX experiments.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100131"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000084/pdfft?md5=c5f1d40127b05dcec44b6c96edc93911&pid=1-s2.0-S2665928X24000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139718264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Doxorubicin catalyses self-assembly of p53 by phase separation","authors":"Ankush Garg ,&nbsp;Gaurav Kumar ,&nbsp;Varinder Singh ,&nbsp;Sharmistha Sinha","doi":"10.1016/j.crstbi.2024.100133","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100133","url":null,"abstract":"<div><p>Liquid-liquid phase separation plays a crucial role in cellular physiology, as it leads to the formation of membrane-less organelles in response to various internal stimuli, contributing to various cellular functions. However, the influence of exogenous stimuli on this process in the context of disease intervention remains unexplored. In this current investigation, we explore the impact of doxorubicin on the abnormal self-assembly of p53 using a combination of biophysical and imaging techniques. Additionally, we shed light on the potential mechanisms behind chemoresistance in cancer cells carrying mutant p53.</p><p>Our findings reveal that doxorubicin co-localizes with both wild-type p53 (WTp53) and its mutant variants. Our <em>in vitro</em> experiments indicate that doxorubicin interacts with the N-terminal-deleted form of WTp53 (WTp53ΔNterm), inducing liquid-liquid phase separation, ultimately leading to protein aggregation. Notably, the p53 variants at the R273 position exhibit a propensity for phase separation even in the absence of doxorubicin, highlighting the destabilizing effects of point mutations at this position.</p><p>The strong interaction between doxorubicin and p53 variants, along with its localization within the protein condensates, provides a potential explanation for the development of chemotherapy resistance. Collectively, our cellular and <em>in vitro</em> studies emphasize the role of exogenous agents in driving phase separation-mediated p53 aggregation.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100133"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000102/pdfft?md5=42fe7a839b8535990a75792d8a30bcc4&pid=1-s2.0-S2665928X24000102-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139936977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural insights into the disulfide isomerase and chaperone activity of TrbB of the F plasmid type IV secretion system","authors":"Arnold J. Apostol ,&nbsp;Nicholas J. Bragagnolo ,&nbsp;Christina S. Rodriguez ,&nbsp;Gerald F. Audette","doi":"10.1016/j.crstbi.2024.100156","DOIUrl":"10.1016/j.crstbi.2024.100156","url":null,"abstract":"<div><p>Bacteria have evolved elaborate mechanisms to thrive in stressful environments. F-like plasmids in gram-negative bacteria encode for a multi-protein Type IV Secretion System (T4SS_F) that is functional for bacterial proliferation and adaptation through the process of conjugation. The periplasmic protein TrbB is believed to have a stabilizing chaperone role in the T4SS_F assembly, with TrbB exhibiting disulfide isomerase (DI) activity. In the current report, we demonstrate that the deletion of the disordered N-terminus of TrbB_WT, resulting in a truncation construct TrbB_37-161, does not affect its catalytic <em>in vitro</em> activity compared to the wild-type protein (p = 0.76). Residues W37–K161, which include the active thioredoxin motif, are sufficient for DI activity. The N-terminus of TrbB_WT is disordered as indicated by a structural model of GST-TrbB_WT based on ColabFold-AlphaFold2 and Small Angle X-Ray Scattering data and ¹H–¹⁵N Heteronuclear Single Quantum Correlation (HSQC) spectroscopy of the untagged protein. This disordered region likely contributes to the protein's dynamicity; removal of this region results in a more stable protein based on ¹H–¹⁵N HSQC and Circular Dichroism Spectroscopies. Lastly, size exclusion chromatography analysis of TrbB_WT in the presence of TraW, a T4SS_F assembly protein predicted to interact with TrbB_WT, does not support the inference of a stable complex forming <em>in vitro</em>. This work advances our understanding of TrbB's structure and function, explores the role of structural disorder in protein dynamics in the context of a T4SS_F accessory protein, and highlights the importance of redox-assisted protein folding in the T4SS_F.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"8 ","pages":"Article 100156"},"PeriodicalIF":2.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000333/pdfft?md5=dd89ce99d737f5e271b30cb1909da8ae&pid=1-s2.0-S2665928X24000333-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural flavonoid pectolinarin computationally targeted as a promising drug candidate against SARS-CoV-2","authors":"Mukta Rani ,&nbsp;Amit Kumar Sharma ,&nbsp;R.S. Chouhan ,&nbsp;Souvik Sur ,&nbsp;Rani Mansuri ,&nbsp;Rajesh K. Singh","doi":"10.1016/j.crstbi.2023.100120","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100120","url":null,"abstract":"<div><p>Coronavirus disease-2019 (COVID-19) has become a global pandemic, necessitating the development of new medicines. In this investigation, we identified potential natural flavonoids and compared their inhibitory activity against spike glycoprotein, which is a target of SARS-CoV-2 and SARS-CoV. The target site for the interaction of new inhibitors for the treatment of SARS-CoV-2 has 82% sequence identity and the remaining 18% dissimilarities in RBD S1-subunit, S2-subunit, and 2.5% others. Molecular docking was employed to analyse the various binding processes used by each ligand in a library of 85 natural flavonoids that act as anti-viral medications and FDA authorised treatments for COVID-19. In the binding pocket of the target active site, remdesivir has less binding interaction than pectolinarin, according to the docking analysis. Pectolinarin is a natural flavonoid isolated from Cirsiumsetidensas that has anti-cancer, vasorelaxant, anti-inflammatory, hepatoprotective, anti-diabetic, anti-microbial, and anti-oxidant properties. The S-glycoprotein RBD region (330–583) is inhibited by kaempferol, rhoifolin, and herbacetin, but the S2 subunit (686–1270) is inhibited by pectolinarin, morin, and remdesivir. MD simulation analysis of S-glycoprotein of SARS-CoV-2 with pectolinarin complex at 100ns based on high dock-score. Finally, ADMET analysis was used to validate the proposed compounds with the highest binding energy.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100120"},"PeriodicalIF":2.8,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000260/pdfft?md5=0876e4e16473c3913893c6e531b0f969&pid=1-s2.0-S2665928X23000260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138839521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Probing the ligand binding specificity of FNBP4 WW domains and interaction with FH1 domain of FMN1","authors":"Shubham Das,&nbsp;Sankar Maiti","doi":"10.1016/j.crstbi.2023.100119","DOIUrl":"https://doi.org/10.1016/j.crstbi.2023.100119","url":null,"abstract":"<div><p>Formins are a group of actin-binding proteins that mediate nascent actin filament polymerization, filament elongation, and barbed end-capping function, thereby regulating different cellular and developmental processes. Developmental processes like vertebrate gastrulation, neural growth cone dynamics, and limb development require formins functioning in a regulated manner. Formin-binding proteins like Rho GTPase regulate the activation of auto-inhibited conformation of diaphanous formins. Unlike other diaphanous formins, Formin1 (FMN1) a non-diaphanous formin is not regulated by Rho GTPase. FMN1 acts as an antagonist of the Bone Morphogenetic Protein (BMP) signaling pathway during limb development. Several previous reports demonstrated that WW domain-containing proteins can interact with poly-proline-rich amino acid stretches of formins and play a crucial role in developmental processes. In contrast, WW domain-containing Formin-binding Protein 4 <strong>(</strong>FNBP4) protein plays an essential role in limb development. It has been hypothesized that the interaction between FNBP4 and FMN1 can further attribute to the role in limb development through the BMP signaling pathway. In this study, we have elucidated the binding kinetics of FNBP4 and FMN1 using surface plasmon resonance (SPR) and enzyme-linked immunosorbent assays (ELISA). Our findings confirm that the FNBP4 exhibits interaction with the poly-proline-rich formin homology 1 (FH1) domain of FMN1. Furthermore, only the first WW1 domains are involved in the interaction between the two domains. Thus, this study sheds light on the binding potentialities of WW domains of FNBP4 that might contribute to the regulation of FMN1 function.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100119"},"PeriodicalIF":2.8,"publicationDate":"2023-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000259/pdfft?md5=557180547c083e1b71ac124aa7c4ebf4&pid=1-s2.0-S2665928X23000259-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138656205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Studying early structural changes in SOS1 mediated KRAS activation mechanism","authors":"Kirti Bhadhadhara,&nbsp;Vinod Jani,&nbsp;Shruti Koulgi,&nbsp;Uddhavesh Sonavane,&nbsp;Rajendra Joshi","doi":"10.1016/j.crstbi.2023.100115","DOIUrl":"10.1016/j.crstbi.2023.100115","url":null,"abstract":"<div><p>KRAS activation is known to be modulated by a guanine nucleotide exchange factor (GEF), namely, Son of Sevenless1 (SOS1). SOS1 facilitates the exchange of GDP to GTP thereby leading to activation of KRAS. The binding of GDP/GTP to KRAS at the REM/allosteric site of SOS1 regulates the activation of KRAS at CDC25/catalytic site by facilitating its exchange. Different aspects of the allosteric activation of KRAS through SOS1 are still being explored. To understand the SOS1 mediated activation of KRAS, molecular dynamics simulations for a total of nine SOS1 complexes (KRAS-SOS1-KRAS) were performed. These nine systems comprised different combinations of KRAS-bound nucleotides (GTP/GDP) at REM and CDC25 sites of SOS1. Various conformational and thermodynamic parameters were analyzed for these simulation systems. MMPBSA free energy analysis revealed that binding at CDC25 site of SOS1 was significantly low for GDP-bound KRAS as compared to that of GTP-bound KRAS. It was observed that presence of either GDP/GTP bound KRAS at the REM site of SOS1 affected the activation related changes in the KRAS present at CDC25 site. The conformational changes at the catalytic site of SOS1 resulting from GDP/GTP-bound KRAS at the allosteric changes may hint at KRAS activation through different pathways (slow/fast/rare). The allosteric effect on activation of KRAS at CDC25 site may be due to conformations adopted by switch-I, switch-II, beta2 regions of KRAS at REM site. The effect of structural rearrangements occurring at allosteric KRAS may have led to increased interactions between SOS1 and KRAS at both the sites. The SOS1 residues involved in these important interactions with KRAS at the REM site were R694, S732 and K735. Whereas the ones interacting with KRAS at CDC25 site were S807, W809 and K814. This may suggest the crucial role of these residues in guiding the allosteric activation of KRAS at CDC25 site. The conformational shifts observed in the switch-I, switch-II and alpha3 regions of KRAS at CDC25 site may be attributed to be a part of allosteric activation. The binding affinities, interacting residues and conformational dynamics may provide an insight into development of inhibitors targeting the SOS1 mediated KRAS activation.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100115"},"PeriodicalIF":2.8,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000211/pdfft?md5=ba23f86d71877bd6e14dd387ed507c59&pid=1-s2.0-S2665928X23000211-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138624605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}