Journal of Molecular Biology最新文献

{"title":"Human CST Stimulates Base Excision Repair to Prevent the Accumulation of Oxidative DNA Damage","authors":"Brandon C. Wysong ,&nbsp;P. Logan Schuck ,&nbsp;Madhumita Sridharan ,&nbsp;Sophie Carrison ,&nbsp;Yuichihiro Murakami ,&nbsp;Lata Balakrishnan ,&nbsp;Jason A. Stewart","doi":"10.1016/j.jmb.2024.168672","DOIUrl":"10.1016/j.jmb.2024.168672","url":null,"abstract":"<div><p>CTC1-STN1-TEN1 (CST) is a single-stranded DNA binding protein vital for telomere length maintenance with additional genome-wide roles in DNA replication and repair. While CST was previously shown to function in double-strand break repair and promote replication restart, it is currently unclear whether it has specialized roles in other DNA repair pathways. Proper and efficient repair of DNA is critical to protecting genome integrity. Telomeres and other G-rich regions are strongly predisposed to oxidative DNA damage in the form of 8-oxoguanines, which are typically repaired by the base-excision repair (BER) pathway. Moreover, recent studies suggest that CST functions in the repair of oxidative DNA lesions. Therefore, we tested whether CST interacts with and regulates BER protein activity. Here, we show that CST robustly stimulates proteins involved in BER, including OGG1, Pol β, APE1, and LIGI, on both telomeric and non-telomeric DNA substrates. Biochemical reconstitution of the pathway indicates that CST stimulates BER. Finally, knockout of STN1 or CTC1 leads to increased levels of 8-oxoguanine, suggesting defective BER in the absence of CST. Combined, our results define an undiscovered function of CST in BER, where it acts as a stimulatory factor to promote efficient genome-wide oxidative repair.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624002675/pdfft?md5=b472cd6e4b175524b1c67e8441510e9d&pid=1-s2.0-S0022283624002675-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Structure and Function of the Bacterial Osmotically Inducible Protein Y","authors":"Aditya Iyer ,&nbsp;Jacopo Frallicciardi ,&nbsp;Ulric B.A. le Paige ,&nbsp;Siddarth Narasimhan ,&nbsp;Yanzhang Luo ,&nbsp;Patricia Alvarez Sieiro ,&nbsp;Lukasz Syga ,&nbsp;Floris van den Brekel ,&nbsp;Buu Minh Tran ,&nbsp;Rendy Tjioe ,&nbsp;Gea Schuurman-Wolters ,&nbsp;Marc C.A. Stuart ,&nbsp;Marc Baldus ,&nbsp;Hugo van Ingen ,&nbsp;Bert Poolman","doi":"10.1016/j.jmb.2024.168668","DOIUrl":"10.1016/j.jmb.2024.168668","url":null,"abstract":"<div><p>The ability to adapt to osmotically diverse and fluctuating environments is critical to the survival and resilience of bacteria that colonize the human gut and urinary tract. Environmental stress often provides cross-protection against other challenges and increases antibiotic tolerance of bacteria. Thus, it is critical to understand how <em>E. coli</em> and other microbes survive and adapt to stress conditions. The osmotically inducible protein Y (OsmY) is significantly upregulated in response to hypertonicity. Yet its function remains unknown for decades. We determined the solution structure and dynamics of OsmY by nuclear magnetic resonance spectroscopy, which revealed that the two Bacterial OsmY and Nodulation (BON) domains of the protein are flexibly linked under low- and high-salinity conditions. In-cell solid-state NMR further indicates that there are no gross structural changes in OsmY as a function of osmotic stress. Using cryo-electron and super-resolution fluorescence microscopy, we show that OsmY attenuates plasmolysis-induced structural changes in <em>E. coli</em> and improves the time to growth resumption after osmotic upshift. Structure-guided mutational and functional studies demonstrate that exposed hydrophobic residues in the BON1 domain are critical for the function of OsmY. We find no evidence for membrane interaction of the BON domains of OsmY, contrary to current assumptions. Instead, at high ionic strength, we observe an interaction with the water channel, AqpZ. Thus, OsmY does not play a simple structural role in <em>E. coli</em> but may influence a cascade of osmoregulatory functions of the cell.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624002638/pdfft?md5=ce11fc27e2874e42e0edb34581422041&pid=1-s2.0-S0022283624002638-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mono- and Bi-specific Nanobodies Targeting the CUB Domains of PCPE-1 Reduce the Proteolytic Processing of Fibrillar Procollagens","authors":"Priscillia Lagoutte ,&nbsp;Jean-Marie Bourhis ,&nbsp;Natacha Mariano ,&nbsp;Virginie Gueguen-Chaignon ,&nbsp;David Vandroux ,&nbsp;Catherine Moali ,&nbsp;Sandrine Vadon-Le Goff","doi":"10.1016/j.jmb.2024.168667","DOIUrl":"10.1016/j.jmb.2024.168667","url":null,"abstract":"<div><p>The excessive deposition of fibrillar collagens is a hallmark of fibrosis. Collagen fibril formation requires proteolytic maturations by Procollagen N- and C-proteinases (PNPs and PCPs) to remove the N- and C-propeptides which maintain procollagens in the soluble form. Procollagen C-Proteinase Enhancer-1 (PCPE-1, a glycoprotein composed of two CUB domains and one NTR domain) is a regulatory protein that activates the C-terminal processing of procollagens by the main PCPs. It is often up-regulated in fibrotic diseases and represents a promising target for the development of novel anti-fibrotic strategies.</p><p>Here, our objective was to develop the first antagonists of PCPE-1, based on the nanobody scaffold. Using both an <em>in vivo</em> selection through the immunization of a llama and an <em>in vitro</em> selection with a synthetic library, we generated 18 nanobodies directed against the CUB domains of PCPE1, which carry its enhancing activity. Among them, I5 from the immune library and H4 from the synthetic library have a high affinity for PCPE-1 and inhibit its interaction with procollagens. The crystal structure of the complex formed by PCPE-1, H4 and I5 showed that they have distinct epitopes and enabled the design of a biparatopic fusion, the diabody diab-D1. Diab-D1 has a sub-nanomolar affinity for PCPE-1 and is a potent antagonist of its activity, preventing the stimulation of procollagen cleavage <em>in vitro.</em> Moreover, Diab-D1 is also effective in reducing the proteolytic maturation of procollagen I in cultures of human dermal fibroblasts and hence holds great promise as a tool to modulate collagen deposition in fibrotic conditions.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624002626/pdfft?md5=45415a3c60aa8fec81aa4c0c134ccc57&pid=1-s2.0-S0022283624002626-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141431045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNap Bond, a Crucial Hydrogen Bond Between Ser in Helix 3 and Asn in Helix 4, Regulates the Structural Dynamics of Heliorhodopsin","authors":"Toshiki Nakamura ,&nbsp;Manish Singh ,&nbsp;Masahiro Sugiura ,&nbsp;Soichiro Kato ,&nbsp;Ryo Yamamoto ,&nbsp;Hideki Kandori ,&nbsp;Yuji Furutani","doi":"10.1016/j.jmb.2024.168666","DOIUrl":"10.1016/j.jmb.2024.168666","url":null,"abstract":"<div><p>Heliorhodopsin (HeR) is a new rhodopsin family discovered in 2018 through functional metagenomic analysis. Similar to microbial rhodopsins, HeR has an all-<em>trans</em> retinal chromophore, and its photoisomerization to the 13-<em>cis</em> form triggers a relatively slow photocycle with sequential intermediate states (K, M, and O intermediates). The O intermediate has a relatively long lifetime and is a putative active state for transferring signals or regulating enzymatic reactions. Although the first discovered HeR, 48C12, was found in bacteria and the second HeR (TaHeR) was found in archaea, their key amino acid residues and molecular architectures have been recognized to be well conserved. Nevertheless, the rise and decay kinetics of the O intermediate are faster in 48C12 than in TaHeR. Here, using a new infrared spectroscopic technique with quantum cascade lasers, we clarified that the hydrogen bond between transmembrane helices (TM) 3 and 4 is essential for the altered O kinetics (Ser112 and Asn138 in 48C12). Interconverting mutants of 48C12 and TaHeR clearly revealed that the hydrogen bond is important for regulating the dynamics of the O intermediate. Overall, our study sheds light on the importance of the hydrogen bond between TM3 and TM4 in heliorhodopsins, similar to the DC gate in channelrhodopsins.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624002614/pdfft?md5=756e9d602b8ef17541095027a93f9011&pid=1-s2.0-S0022283624002614-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141329964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Binder Toolbox for Studies of Solute Carrier Transporters","authors":"Zuzana Gelová ,&nbsp;Alvaro Ingles-Prieto ,&nbsp;Tina Bohstedt ,&nbsp;Fabian Frommelt ,&nbsp;Gamma Chi ,&nbsp;Yung-Ning Chang ,&nbsp;Julio Garcia ,&nbsp;Gernot Wolf ,&nbsp;Lucia Azzollini ,&nbsp;Sara Tremolada ,&nbsp;Andreea Scacioc ,&nbsp;Jesper S. Hansen ,&nbsp;Iciar Serrano ,&nbsp;Aida Droce ,&nbsp;Jenifer Cuesta Bernal ,&nbsp;Nicola A. Burgess-Brown ,&nbsp;Elisabeth P. Carpenter ,&nbsp;Katharina L. Dürr ,&nbsp;Peter Kristensen ,&nbsp;Eric R. Geertsma ,&nbsp;Giulio Superti-Furga","doi":"10.1016/j.jmb.2024.168665","DOIUrl":"10.1016/j.jmb.2024.168665","url":null,"abstract":"<div><p>Transporters of the solute carrier superfamily (SLCs) are responsible for the transmembrane traffic of the majority of chemical substances in cells and tissues and are therefore of fundamental biological importance. As is often the case with membrane proteins that can be heavily glycosylated, a lack of reliable high-affinity binders hinders their functional analysis. Purifying and reconstituting transmembrane proteins in their lipidic environments remains challenging and standard approaches to generate binders for multi-transmembrane proteins, such as SLCs, channels or G protein-coupled receptors (GPCRs) are lacking. While generating protein binders to 27 SLCs, we produced full length protein or cell lines as input material for binder generation by selected binder generation platforms. As a result, we obtained 525 binders for 22 SLCs. We validated the binders with a cell-based validation workflow using immunofluorescent and immunoprecipitation methods to process all obtained binders. Finally, we demonstrated the potential applications of the binders that passed our validation pipeline in structural, biochemical, and biological applications using the exemplary protein SLC12A6, an ion transporter relevant in human disease. With this work, we were able to generate easily renewable and highly specific binders against SLCs, which will greatly facilitate the study of this neglected protein family. We hope that the process will serve as blueprint for the generation of binders against the entire superfamily of SLC transporters.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prediction of Recombination Hotspot Based on Automated Machine Learning.","authors":"Dong-Xin Ye, Jun-Wen Yu, Rui Li, Yu-Duo Hao, Tian-Yu Wang, Hui Yang, Hui Ding","doi":"10.1016/j.jmb.2024.168653","DOIUrl":"10.1016/j.jmb.2024.168653","url":null,"abstract":"<p><p>Meiotic recombination plays a pivotal role in genetic evolution. Genetic variation induced by recombination is a crucial factor in generating biodiversity and a driving force for evolution. At present, the development of recombination hotspot prediction methods has encountered challenges related to insufficient feature extraction and limited generalization capabilities. This paper focused on the research of recombination hotspot prediction methods. We explored deep learning-based recombination hotspot prediction and scrutinized the shortcomings of prevalent models in addressing the challenge of recombination hotspot prediction. To addressing these deficiencies, an automated machine learning approach was utilized to construct recombination hotspot prediction model. The model combined sequence information with physicochemical properties by employing TF-IDF-Kmer and DNA composition components to acquire more effective feature data. Experimental results validate the effectiveness of the feature extraction method and automated machine learning technology used in this study. The final model was validated on three distinct datasets and yielded accuracy rates of 97.14%, 79.71%, and 98.73%, surpassing the current leading models by 2%, 2.56%, and 4%, respectively. In addition, we incorporated tools such as SHAP and AutoGluon to analyze the interpretability of black-box models, delved into the impact of individual features on the results, and investigated the reasons behind misclassification of samples. Finally, an application of recombination hotspot prediction was established to facilitate easy access to necessary information and tools for researchers. The research outcomes of this paper underscore the enormous potential of automated machine learning methods in gene sequence prediction.</p>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special Issue: Proteostasis and Protein Quality Control","authors":"Johannes Buchner","doi":"10.1016/j.jmb.2024.168664","DOIUrl":"10.1016/j.jmb.2024.168664","url":null,"abstract":"","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022283624002596/pdfft?md5=ef498920e9a33698ffcc6aca72495443&pid=1-s2.0-S0022283624002596-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and Characterization of Two Folded Intermediates for Outer Membrane Protein TolC Biogenesis","authors":"Ayotunde Paul Ikujuni ,&nbsp;Rik Dhar ,&nbsp;Andres Cordova ,&nbsp;Alexander M. Bowman ,&nbsp;Sarah Noga ,&nbsp;Joanna S.G. Slusky","doi":"10.1016/j.jmb.2024.168652","DOIUrl":"10.1016/j.jmb.2024.168652","url":null,"abstract":"<div><p>TolC is the outer membrane protein responsible for antibiotic efflux in <em>E. coli</em>. Compared to other outer membrane proteins it has an unusual fold and has been shown to fold independently of commonly used periplasmic chaperones, SurA and Skp. Here we find that the assembly of TolC involves the formation of two folded intermediates using circular dichroism, gel electrophoresis, site-specific disulfide bond formation and radioactive labeling. First the TolC monomer folds, and then TolC assembles into a trimer both in detergent-free buffer and in the presence of detergent micelles. We find that a TolC trimer also forms in the periplasm and is present in the periplasm before it inserts in the outer membrane. The monomeric and trimeric folding intermediates may be used in the future to develop a new approach to antibiotic efflux pump inhibition by targeting the assembly pathway of TolC.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002228362400247X/pdfft?md5=be81b8288231b44046c43934684d5691&pid=1-s2.0-S002228362400247X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"C-terminal Poly-histidine Tags Alter Escherichia coli Polyphosphate Kinase Activity and Susceptibility to Inhibition","authors":"Marvin Q. Bowlin,&nbsp;Avery D. Lieber,&nbsp;Abagail R. Long ,&nbsp;Michael J. Gray","doi":"10.1016/j.jmb.2024.168651","DOIUrl":"10.1016/j.jmb.2024.168651","url":null,"abstract":"<div><p>In <em>Escherichia coli</em>, many environmental stressors trigger polyphosphate (polyP) synthesis by polyphosphate kinase (PPK1), including heat, nutrient restriction, toxic compounds, and osmotic imbalances. PPK1 is essential for virulence in many pathogens and has been the target of multiple screens for small molecule inhibitors that might serve as new anti-virulence drugs. However, the mechanisms by which PPK1 activity and polyP synthesis are regulated are poorly understood. Our previous attempts to uncover PPK1 regulatory elements resulted in the discovery of PPK1* mutants, which accumulate more polyP <em>in vivo</em>, but do not produce more <em>in vitro</em>. In attempting to further characterize these mutant enzymes, we discovered that the most commonly-used PPK1 purification method – Ni-affinity chromatography using a C-terminal poly-histidine tag – altered intrinsic aspects of the PPK1 enzyme, including specific activity, oligomeric state, and kinetic values. We developed an alternative purification strategy using a C-terminal C-tag which did not have these effects. Using this strategy, we were able to demonstrate major differences in the <em>in vitro</em> response of PPK1 to 5-aminosalicylic acid, a known PPK1 inhibitor, and observed several key differences between the wild-type and PPK1* enzymes, including changes in oligomeric distribution, increased enzymatic activity, and increased resistance to both product (ADP) and substrate (ATP) inhibition, that help to explain their <em>in vivo</em> effects. Importantly, our results indicate that the C-terminal poly-histidine tag is inappropriate for purification of PPK1, and that any <em>in vitro</em> studies or inhibitor screens performed with such tags need to be reconsidered in that light.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure and Interactions of HIV-1 gp41 CHR-NHR Reverse Hairpin Constructs Reveal Molecular Determinants of Antiviral Activity","authors":"Li He ,&nbsp;Ryan McAndrew ,&nbsp;Razvan Barbu ,&nbsp;Grant Gifford ,&nbsp;Cari Halacoglu ,&nbsp;Camille Drouin-Allaire ,&nbsp;Lindsey Weber ,&nbsp;Line G. Kristensen ,&nbsp;Sayan Gupta ,&nbsp;Yan Chen ,&nbsp;Christopher J. Petzold ,&nbsp;Marc Allaire ,&nbsp;Kathy H. Li ,&nbsp;Corie Y. Ralston ,&nbsp;Miriam Gochin","doi":"10.1016/j.jmb.2024.168650","DOIUrl":"10.1016/j.jmb.2024.168650","url":null,"abstract":"<div><p>Engineered reverse hairpin constructs containing a partial C-heptad repeat (CHR) sequence followed by a short loop and full-length N-heptad repeat (NHR) were previously shown to form trimers in solution and to be nanomolar inhibitors of HIV-1 Env mediated fusion. Their target is the in situ gp41 fusion intermediate, and they have similar potency to other previously reported NHR trimers. However, their design implies that the NHR is partially covered by CHR, which would be expected to limit potency. An exposed hydrophobic pocket in the folded structure may be sufficient to confer the observed potency, or they may exist in a partially unfolded state exposing full length NHR. Here we examined their structure by crystallography, CD and fluorescence, establishing that the proteins are folded hairpins both in crystal form and in solution. We examined unfolding in the milieu of the fusion reaction by conducting experiments in the presence of a membrane mimetic solvent and by engineering a disulfide bond into the structure to prevent partial unfolding. We further examined the role of the hydrophobic pocket, using a hairpin-small molecule adduct that occluded the pocket, as confirmed by X-ray footprinting. The results demonstrated that the NHR region nominally covered by CHR in the engineered constructs and the hydrophobic pocket region that is exposed by design were both essential for nanomolar potency and that interaction with membrane is likely to play a role in promoting the required inhibitor structure. The design concepts can be applied to other Class 1 viral fusion proteins.</p></div>","PeriodicalId":369,"journal":{"name":"Journal of Molecular Biology","volume":null,"pages":null},"PeriodicalIF":4.7,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141309797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}