Current Research in Structural Biology最新文献

{"title":"Computational insights into the circular permutation roles on ConA binding and structural stability","authors":"Vinicius J.S. Osterne ,&nbsp;Vanir R. Pinto-Junior ,&nbsp;Messias V. Oliveira ,&nbsp;Kyria S. Nascimento ,&nbsp;Els J.M. Van Damme ,&nbsp;Benildo S. Cavada","doi":"10.1016/j.crstbi.2024.100140","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100140","url":null,"abstract":"<div><p>The mechanisms behind Concanavalin A (ConA) circular permutation have been under investigation since 1985. Although a vast amount of information is available about this lectin and its applications, the exact purpose of its processing remains unclear. To shed light on this, this study employed computer simulations to compare the unprocessed ProConA with the mature ConA. This approach aimed to reveal the importance of the post-translational modifications, especially how they affect the lectin stability and carbohydrate-binding properties. To achieve these goals, we conducted 200 ns molecular dynamics simulations and trajectory analyses on the monomeric forms of ProConA and ConA (both unbound and in complex with D-mannose and the GlcNAc2Man9 N-glycan), as well as on their oligomeric forms. Our findings reveal significant stability differences between ProConA and ConA at both the monomeric and tetrameric levels, with ProConA exhibiting consistently lower stability parameters compared to ConA. In terms of carbohydrate binding properties, however, both lectins showed remarkable similarities in their interaction profiles, contact numbers, and binding free energies with D-mannose and the high-mannose <em>N</em>-glycan. Overall, our results suggest that the processing of ProConA significantly enhances the stability of the mature lectin, especially in maintaining the tetrameric oligomer, without substantially affecting its carbohydrate-binding properties.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100140"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000175/pdfft?md5=b06094ed529fd6dbc276a5c6062ee665&pid=1-s2.0-S2665928X24000175-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140290612","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":"Integrative modeling of JCVI-Syn3A nucleoids with a modular approach","authors":"David S. Goodsell ,&nbsp;Ludovic Autin","doi":"10.1016/j.crstbi.2023.100121","DOIUrl":"10.1016/j.crstbi.2023.100121","url":null,"abstract":"<div><p>A lattice-based method is presented for creating 3D models of entire bacterial nucleoids integrating ultrastructural information cryoelectron tomography, genomic and proteomic data, and experimental atomic structures of biomolecules and assemblies. The method is used to generate models of the minimal genome bacterium JCVI-Syn3A, producing a series of models that test hypotheses about transcription, condensation, and overall distribution of the genome. Lattice models are also used to generate atomic models of an entire JCVI-Syn3A cell.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100121"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X23000272/pdfft?md5=2b6046ee7971c557a79d6bdb88434d6f&pid=1-s2.0-S2665928X23000272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139019360","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":"Evaluating therapeutic potential of AYUSH-64 constituents against omicron variant of SARS-CoV-2 using ensemble docking and simulations","authors":"Vinod Jani ,&nbsp;Shruti Koulgi ,&nbsp;Mallikarjunachari V.N. Uppuladinne ,&nbsp;Saket Ram Thrigulla ,&nbsp;Manohar Gundeti ,&nbsp;Goli Penchala Prasad ,&nbsp;Sanjaya Kumar ,&nbsp;Srikanth Narayanam ,&nbsp;Uddhavesh Sonavane ,&nbsp;Rajendra Joshi","doi":"10.1016/j.crstbi.2024.100151","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100151","url":null,"abstract":"<div><p>The COVID-19 pandemic in the later phase showed the presence of the B.1.1.529 variant of the SARS-CoV-2 designated as Omicron. AYUSH-64 a poly herbal drug developed by Central Council for Research in Ayurvedic Sciences (CCRAS) has been recommended by Ministry of Ayush in asymptomatic, mild to moderate COVID-19 patients. One of the earlier, <em>in-silico</em> study has shown the binding of the constituents of AYUSH-64 to the main protease (M^pro) of the SARS-CoV-2. This study enlisted four phytochemicals of AYUSH-64, which were found to have significant binding with the M^pro. In continuation to the same, the current study proposes to understand the binding of these four phytochemicals to main protease (M^pro) and receptor binding domain (RBD) of spike protein of the Omicron variant. An enhanced molecular docking methodology, namely, ensemble docking has been used to find the most efficiently binding phytochemical. Using molecular dynamics (MD) simulations and clustering approach it was observed that the M^pro and RBD Spike of Omicron variant of SARS-CoV-2 in complex with human ACE2 tends to attain 4 and 8 conformational respectively. Based on the docking studies, the best binding phytochemical of the AYUSH-64, akummicine N-oxide was selected for MD simulations. MD simulations of akummicine N-oxide bound to omicron variant of M^pro and RBD Spike-ACE complex was performed. The conformational, interaction and binding energy analysis suggested that the akummicine N-oxide binds well with M^pro and RBD Spike-ACE2 complex. The interaction between RBD Spike and ACE2 was observed to weaken in the presence of akummicine N-oxide. Hence, it can be inferred that, these phytochemicals from AYUSH-64 formulation may have the potential to act against the Omicron variant of SARS-CoV-2.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100151"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X2400028X/pdfft?md5=836de7f1d95a5e52325b80b7e6600418&pid=1-s2.0-S2665928X2400028X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141244089","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":"2024-01-01","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}

{"title":"Pathogenic single nucleotide polymorphisms in RhoA gene: Insights into structural and functional impacts on RhoA-PLD1 interaction through molecular dynamics simulation","authors":"Mahbub Hasan ,&nbsp;Md. Nayem Sarker ,&nbsp;Tazkia Jabin ,&nbsp;Saifuddin Sarker,&nbsp;Shamim Ahmed,&nbsp;Mohammad Abdullah-Al-Shoeb,&nbsp;Tanvir Hossain","doi":"10.1016/j.crstbi.2024.100159","DOIUrl":"10.1016/j.crstbi.2024.100159","url":null,"abstract":"<div><div>Molecular switches serve as key regulators of biological systems by acting as one of the crucial driving forces in the initiation of signal transduction pathway cascades. The Ras homolog gene family member A (RhoA) is one of the molecular switches that binds with GTP in order to cycle between an active GTP-bound state and an inactive GDP-bound state. Any aberrance in control over this circuit, particularly due to any perturbation in switching, leads to the development of different pathogenicity. Consequently, the single nucleotide polymorphisms (SNPs) within the RhoA gene, especially deleterious genetic variations, are crucial to study to forecast structural alteration and their functional impacts in light of disease onset. In this comprehensive study, we employed a range of computational tools to screen the deleterious SNPs of RhoA from 207 nonsynonymous SNPs (nsSNPs). By utilizing 7 distinct tools for further analysis, 8 common deleterious SNPs were sorted, among them 5 nsSNPs (V9G, G17E, E40K, A61T, F171L) were found to be in the highly conserved regions, with E40K and A61T at G2 and G3 motif of the GTP-binding domain respectively, indicating potential perturbation in GTP/GDP binding ability of the protein. RhoA-GDP complex interacts with the enzyme phospholipase, specifically PLD1, to regulate different cellular activities. PLD1 is also a crucial regulator of thrombosis and cancer. In that line of focus, our initial structural analysis of Y66H, A61T, G17E, I86N, and I151T mutations of RhoA revealed remarkable decreased hydrophobicity from which we further filtered out G17E and I86N which may have potential impact on the RhoA-GDP-PLD1 complex. Intriguingly, the comparative 250 ns (ns) molecular dynamics (MD) simulation of these two mutated complexes revealed overall structural instability and altered interaction patterns. Therefore, further investigation into these deleterious mutations with <em>in vitro</em> and <em>in vivo</em> studies could lead to the identification of potential biomarkers in terms of different pathogenesis and could also be utilized in personalized therapeutic targets in the long run.</div></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"8 ","pages":"Article 100159"},"PeriodicalIF":2.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11653153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853227","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":"Bacterial selenocysteine synthase structure revealed by single-particle cryoEM","authors":"Vitor Hugo Balasco Serrão ,&nbsp;Karine Minari ,&nbsp;Humberto D'Muniz Pereira ,&nbsp;Otavio Henrique Thiemann","doi":"10.1016/j.crstbi.2024.100143","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100143","url":null,"abstract":"<div><p>The 21st amino acid, selenocysteine (Sec), is synthesized on its dedicated transfer RNA (tRNA^Sec). In bacteria, Sec is synthesized from Ser-tRNA^[Ser]Sec by Selenocysteine Synthase (SelA), which is a pivotal enzyme in the biosynthesis of Sec. The structural characterization of bacterial SelA is of paramount importance to decipher its catalytic mechanism and its role in the regulation of the Sec-synthesis pathway. Here, we present a comprehensive single-particle cryo-electron microscopy (SPA cryoEM) structure of the bacterial SelA with an overall resolution of 2.69 Å. Using recombinant <em>Escherichia coli</em> SelA, we purified and prepared samples for single-particle cryoEM. The structural insights from SelA, combined with previous <em>in vivo</em> and <em>in vitro</em> knowledge, underscore the indispensable role of decamerization in SelA's function. Moreover, our structural analysis corroborates previous results that show that SelA adopts a pentamer of dimers configuration, and the active site architecture, substrate binding pocket, and key K295 catalytic residue are identified and described in detail. The differences in protein architecture and substrate coordination between the bacterial enzyme and its counterparts offer compelling structural evidence supporting the independent molecular evolution of the bacterial and archaea/eukarya Ser-Sec biosynthesis present in the natural world.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100143"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000205/pdfft?md5=61e3be36dda3b09031c6347f51a91207&pid=1-s2.0-S2665928X24000205-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140558413","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":"2024-01-01","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":"Experimental methods to study the structure and dynamics of intrinsically disordered regions in proteins","authors":"Snigdha Maiti ,&nbsp;Aakanksha Singh,&nbsp;Tanisha Maji,&nbsp;Nikita V. Saibo,&nbsp;Soumya De","doi":"10.1016/j.crstbi.2024.100138","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100138","url":null,"abstract":"<div><p>Eukaryotic proteins often feature long stretches of amino acids that lack a well-defined three-dimensional structure and are referred to as intrinsically disordered proteins (IDPs) or regions (IDRs). Although these proteins challenge conventional structure-function paradigms, they play vital roles in cellular processes. Recent progress in experimental techniques, such as NMR spectroscopy, single molecule FRET, high speed AFM and SAXS, have provided valuable insights into the biophysical basis of IDP function. This review discusses the advancements made in these techniques particularly for the study of disordered regions in proteins. In NMR spectroscopy new strategies such as ¹³C detection, non-uniform sampling, segmental isotope labeling, and rapid data acquisition methods address the challenges posed by spectral overcrowding and low stability of IDPs. The importance of various NMR parameters, including chemical shifts, hydrogen exchange rates, and relaxation measurements, to reveal transient secondary structures within IDRs and IDPs are presented. Given the high flexibility of IDPs, the review outlines NMR methods for assessing their dynamics at both fast (ps-ns) and slow (μs-ms) timescales. IDPs exert their functions through interactions with other molecules such as proteins, DNA, or RNA. NMR-based titration experiments yield insights into the thermodynamics and kinetics of these interactions. Detailed study of IDPs requires multiple experimental techniques, and thus, several methods are described for studying disordered proteins, highlighting their respective advantages and limitations. The potential for integrating these complementary techniques, each offering unique perspectives, is explored to achieve a comprehensive understanding of IDPs.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100138"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000151/pdfft?md5=f40c41eba2b2db9f84e2f421c05b2b24&pid=1-s2.0-S2665928X24000151-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140807179","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":"Structure-function analyses reveal Arabidopsis thaliana HDA7 to be an inactive histone deacetylase","authors":"Ketul Saharan ,&nbsp;Somanath Baral ,&nbsp;Nausad Hossain Shaikh ,&nbsp;Dileep Vasudevan","doi":"10.1016/j.crstbi.2024.100136","DOIUrl":"https://doi.org/10.1016/j.crstbi.2024.100136","url":null,"abstract":"<div><p>Histone deacetylases (HDACs), responsible for the removal of acetyl groups from histone tails, are important epigenetic factors. They play a critical role in the regulation of gene expression and are significant in the context of plant growth and development. The Rpd3/Hda1 family of HDACs is reported to regulate key biological processes in plants, such as stress response, seed, embryonic, and floral development. Here, we characterized <em>Arabidopsis thaliana</em> HDA7, a Class I, Rpd3/Hda1 family HDAC. SAXS and AUC results show that the recombinantly expressed and purified histone deacetylase domain of AtHDA7 exists as a monomer in solution. Further, the crystal structure showed AtHDA7 to fold into the typical α/β arginase fold, characteristic of Rpd3/Hda1 family HDACs. Sequence analysis revealed that the Asp and His residues of the catalytic ‘XDXH’ motif present in functional Rpd3/Hda1 family HDACs are mutated to Gly and Pro, respectively, in AtHDA7, suggesting that it might be catalytically inactive. The Asp and His residues are important for Zn²⁺-binding. Not surprisingly, the crystal structure did not have Zn²⁺ bound in the catalytic pocket, which is essential for the HDAC activity. Further, our <em>in vitro</em> activity assay revealed AtHDA7 to be inactive as an HDAC. A search in the sequence databases suggested that homologs of AtHDA7 are found exclusively in the Brassicaceae family to which Arabidopsis belongs. It is possible that HDA7 descended from HDA6 through whole genome duplication and triplication events during evolution, as suggested in a previous phylogenetic study.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100136"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000138/pdfft?md5=9613b556bf68eed37357f5c1262013ad&pid=1-s2.0-S2665928X24000138-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140014121","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":"Mechanism of drug resistance in HIV-1 protease subtype C in the presence of Atazanavir","authors":"S.V. Sankaran ,&nbsp;Sowmya R. Krishnan ,&nbsp;Yasien Sayed ,&nbsp;M. Michael Gromiha","doi":"10.1016/j.crstbi.2024.100132","DOIUrl":"10.1016/j.crstbi.2024.100132","url":null,"abstract":"<div><p>AIDS is one of the deadliest diseases in the history of humankind caused by HIV. Despite the technological development, curtailing the viral infection inside human host still remains a challenge. Therapies such as HAART uses a combination of drugs to inhibit the viral activity. One of the important targets includes HIV protease and inhibiting its activity will minimize the production of mature structural proteins. However, the genetic diversity and the occurrence of drug resistant mutations adds complexity to effective drug design. In this study, we aimed at understanding the drug binding mechanism of one such subtype, namely subtype C and its insertion variant L38HL. We performed multiple molecular dynamics simulations along with binding free energy analysis of wild-type and L38HL bound to Atazanavir (ATV). From the analysis, we revealed that the insertion alters the hydrogen bond and hydrophobic interaction networks. The alterations in the interaction networks increase flexibility at the hinge-fulcrum interface. Further, the effects of these changes affect flap tip curling. Moreover, the changes in the hinge-fulcrum-cantilever interface alters the concerted motion of the functional regions leading to change in the direction of flap movement thus causing a subtle change in the active site volume. Additionally, formation of intramolecular hydrogen bonds in the ATV docked to L38HL restricted the movement of R1 and R2 groups thereby altering the interactions. Overall, the changes in the flexibility of flap together with the changes in the active site volume and compactness of the ligand provide insights for increased binding affinity of ATV with L38HL.</p></div>","PeriodicalId":10870,"journal":{"name":"Current Research in Structural Biology","volume":"7 ","pages":"Article 100132"},"PeriodicalIF":2.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665928X24000096/pdfft?md5=306b72342c5038d99b11a59449839fde&pid=1-s2.0-S2665928X24000096-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139966445","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}