Structure最新文献_第5页

Direct effect of membrane environment on the activation of mGluR2 revealed by single-molecule FRET

IF 5.7 2区生物学

Structure Pub Date : 2025-02-04 DOI: 10.1016/j.str.2025.01.011

Chiranjib Banerjee, Brandon Wey-Hung Liauw, Reza Vafabakhsh

{"title":"Direct effect of membrane environment on the activation of mGluR2 revealed by single-molecule FRET","authors":"Chiranjib Banerjee, Brandon Wey-Hung Liauw, Reza Vafabakhsh","doi":"10.1016/j.str.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.011","url":null,"abstract":"The microenvironment of membrane receptors controls their mobility, structure, interactions, and dynamics, but a systematic understanding of how it modulates receptor function is often lacking. Using single-molecule Förster resonance energy transfer (smFRET), we characterized how detergents and cholesterol modulate the conformational dynamics of metabotropic glutamate receptor 2 (mGluR2), a class C G protein-coupled receptor (GPCR). We found that, within the resolution of our measurements, all tested detergents stabilize the same overall active and inactive structure of different domains of mGluR2. However, the degree of stabilization and the equilibrium between active and inactive conformations depended on the detergent. Detergents with a single hydrophobic tail increased the active state occupancy compared to those with long, branched tails. Adding cholesterol to micelles with branched hydrophobic tails shifted the equilibrium toward the inactive state. Mutagenesis identified residues potentially involved in cholesterol interaction with mGluR2. Targeting the cholesterol-binding site with synthetic molecules could be a viable therapeutic approach.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"6 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083570","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}

引用次数: 0

The structure of a NEMO construct engineered for screening reveals novel determinants of inhibition

IF 5.7 2区生物学

Structure Pub Date : 2025-02-04 DOI: 10.1016/j.str.2025.01.010

Amy E. Kennedy, Adam H. Barczewski, Christina R. Arnoldy, J. Pepper Pennington, Kelly A. Tiernan, M. Beatriz Hidalgo, Caroline C. Reilly, Tanyawan Wongsri, Michael J. Ragusa, Gevorg Grigoryan, Dale F. Mierke, Maria Pellegrini

{"title":"The structure of a NEMO construct engineered for screening reveals novel determinants of inhibition","authors":"Amy E. Kennedy, Adam H. Barczewski, Christina R. Arnoldy, J. Pepper Pennington, Kelly A. Tiernan, M. Beatriz Hidalgo, Caroline C. Reilly, Tanyawan Wongsri, Michael J. Ragusa, Gevorg Grigoryan, Dale F. Mierke, Maria Pellegrini","doi":"10.1016/j.str.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.010","url":null,"abstract":"NEMO is an essential component in the activation of the canonical nuclear factor κB (NF-κB) pathway and exerts its function by recruiting the IκB kinases (IKK) to the IKK complex. Inhibition of the NEMO/IKKs interaction is an attractive therapeutic paradigm for diseases related to NF-κB mis-regulation, but a difficult endeavor because of the extensive protein-protein interface. Here we report the design and characterization of novel engineered constructs of the IKK-binding domain of NEMO, programmed to render this difficult protein domain amenable to NMR measurements and crystallization, while preserving its biological function. ZipNEMO binds IKKβ with nanomolar affinity, is amenable to heteronuclear nuclear magnetic resonance (NMR) techniques and structure determination by X-ray crystallography. We show that NMR spectra of zipNEMO allow to detect inhibitor binding in solution and resonance assignment. The crystal structure of zipNEMO reveals a novel ligand binding motif and the adaptability of the binding pocket and inspired the design of new peptide inhibitors.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"61 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083568","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}

引用次数: 0

Architecture of an embracing lipase-foldase complex of the type II secretion system of Acinetobacter baumannii

IF 5.7 2区生物学

Structure Pub Date : 2025-02-03 DOI: 10.1016/j.str.2024.12.022

Yuri Rafael de Oliveira Silva, Carlos Contreras-Martel, Ricardo Rodrigues de Melo, Letícia Maria Zanphorlin, Daniel Maragno Trindade, Andréa Dessen

{"title":"Architecture of an embracing lipase-foldase complex of the type II secretion system of Acinetobacter baumannii","authors":"Yuri Rafael de Oliveira Silva, Carlos Contreras-Martel, Ricardo Rodrigues de Melo, Letícia Maria Zanphorlin, Daniel Maragno Trindade, Andréa Dessen","doi":"10.1016/j.str.2024.12.022","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.022","url":null,"abstract":"Acinetobacter baumannii is a major human pathogen responsible for a growing number of multi-antibiotic-resistant infections, and of critical priority for the World Health Organization (WHO). A. baumannii employs a type II secretion system (T2SS) to secrete toxins extracellularly to enable cytotoxicity and colonization. Lipase LipA, secreted by the A. baumannii T2SS, is required for virulence and fitness, and in the periplasm is maintained in an active state by its essential foldase, LipB. Here we report that LipA is able to recognize lipids of different chain lengths at extremes of pH and temperature, thanks to its stabilization by LipB through an extended, highly helical “embrace.” A vast bioinformatic analysis indicates that LipB-like foldases are widespread over numerous proteobacteria, and thus the extended foldase architecture shown here could be widespread. These results provide new insight into A. baumannii’s adaptability as a pathogen in different environments and could facilitate the development of novel antibacterials.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"166 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077199","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}

引用次数: 0

Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor

IF 5.7 2区生物学

Structure Pub Date : 2025-02-03 DOI: 10.1016/j.str.2025.01.008

Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko

{"title":"Structural basis for substrate binding, catalysis and inhibition of cancer target mitochondrial creatine kinase by a covalent inhibitor","authors":"Merve Demir, Laura Koepping, Ya Li, Lynn Fujimoto, Andrey Bobkov, Jianhua Zhao, Taro Hitosugi, Eduard Sergienko","doi":"10.1016/j.str.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.008","url":null,"abstract":"Mitochondrial creatine kinases (MtCKs) are key players in maintaining energy homeostasis in cells that work with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. The inhibition of breast cancer growth by cyclocreatine targeting CKs indicates dependence of cancer cells on the “energy shuttle” for cell growth and survival. Hence, understanding key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics. Herein, we present mutational and structural investigations on understudied ubiquitous MtCK that showed closure of the loop comprising His61 is specific to and relies on creatine binding and mechanism of phosphoryl transfer depends on electrostatics of active site. We demonstrate that previously identified pan-CK covalent inhibitor CKi inhibit breast cancer cell proliferation; however, our biochemical and structural data indicated that inhibition by CKi is highly dependent on covalent link formation and conformational changes upon creatine binding are not observed.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"63 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077190","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}

引用次数: 0

Water occupancy in the Acinetobacter baumannii F-ATP synthase c-ring and its implications as a novel inhibitor target

IF 5.7 2区生物学

Structure Pub Date : 2025-01-31 DOI: 10.1016/j.str.2025.01.004

Alexander Krah, Vandana Grover, Tuck Choy Fong, Peter J. Bond, Gerhard Grüber

{"title":"Water occupancy in the Acinetobacter baumannii F-ATP synthase c-ring and its implications as a novel inhibitor target","authors":"Alexander Krah, Vandana Grover, Tuck Choy Fong, Peter J. Bond, Gerhard Grüber","doi":"10.1016/j.str.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.004","url":null,"abstract":"The Acinetobacter baumannii F1FO-ATP synthase is essential for the opportunistic human pathogen. Its membrane-embedded FO domain consists of the c-ring and subunit a. The c-ring translocates protons via a conserved carboxylate across the membrane via two half-channels in subunit a, and its revolution enables the F1 domain to carry out ATP formation. Here, we used molecular dynamics simulations, free energy calculations, and in vivo mutational experiments to assess the likely existence of water molecules in the binding site of the A. baumannii c-ring. We first predicted its binding site structure in the ion-locked conformation and extrapolated the presence of two water molecules in the ion-binding site. Based on our predictions, amino acid point mutations confirmed the critical role of key residues involved in the water-binding site upon ATP synthesis ability and cell growth. We discuss the implications of our findings in the context of rational drug design to target the A. baumannii FO domain.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"60 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071968","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}

引用次数: 0

Septin assemblies promote the lipid organization of membranes

IF 5.7 2区生物学

Structure Pub Date : 2025-01-31 DOI: 10.1016/j.str.2025.01.005

Fatima El Alaoui, Isabelle Al-Akiki, Sandy Ibanes, Sébastien Lyonnais, David Sanchez-Fuentes, Rudy Desgarceaux, Chantal Cazevieille, Marie-Pierre Blanchard, Andrea Parmeggiani, Adrian Carretero-Genevrier, Simonetta Piatti, Laura Picas

{"title":"Septin assemblies promote the lipid organization of membranes","authors":"Fatima El Alaoui, Isabelle Al-Akiki, Sandy Ibanes, Sébastien Lyonnais, David Sanchez-Fuentes, Rudy Desgarceaux, Chantal Cazevieille, Marie-Pierre Blanchard, Andrea Parmeggiani, Adrian Carretero-Genevrier, Simonetta Piatti, Laura Picas","doi":"10.1016/j.str.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.005","url":null,"abstract":"Cytoskeletal-mediated membrane compartmentalization is essential to support cellular functions, from signaling to cell division, migration, or phagocytosis. Septins are cytoskeletal proteins that directly interact with membranes, acting as scaffolds to recruit proteins to cellular locations and as structural diffusion barriers. How septins interact with and remodel the lipid organization of membranes is unclear. Here, we combined minimal reconstituted systems and yeast cell imaging to study septin-mediated membrane organization. Our results show that at low concentrations membrane-diffusive septins self-assemble into sub-micrometric patches that co-exist with the septin collar at the division site. We found that patches are made of short septin filaments and that are able to modulate the lipid organization of membranes. Furthermore, we show that the polybasic domain of Cdc11 influences the membrane-organizing and curvature-sensing properties of septins. Collectively, our work provides understanding of the molecular mechanisms by which septins can support cellular functions intimately linked to membranes.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"24 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071969","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}

引用次数: 0

Structure of a zoonotic H5N1 hemagglutinin reveals a receptor-binding site occupied by an auto-glycan

IF 5.7 2区生物学

Structure Pub Date : 2025-01-29 DOI: 10.1016/j.str.2025.01.001

Nicholas C. Morano, Yicheng Guo, Jordan E. Becker, Zhiteng Li, Jian Yu, David D. Ho, Lawrence Shapiro, Peter D. Kwong

{"title":"Structure of a zoonotic H5N1 hemagglutinin reveals a receptor-binding site occupied by an auto-glycan","authors":"Nicholas C. Morano, Yicheng Guo, Jordan E. Becker, Zhiteng Li, Jian Yu, David D. Ho, Lawrence Shapiro, Peter D. Kwong","doi":"10.1016/j.str.2025.01.001","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.001","url":null,"abstract":"Highly pathogenic avian influenza has spilled into many mammals, most notably cows and poultry, with several dozen human breakthrough infections. Zoonotic crossovers, with hemagglutinins mutated to enhance viral ability to use human α2-6-linked sialic acid receptors versus avian α2-3-linked ones, highlight the pandemic risk. To gain insight into these crossovers, we determined the cryoelectron microscopy (cryo-EM) structure of the hemagglutinin from the zoonotic H5N1 A/Texas/37/2024 strain (clade 2.3.4.4b) in complex with a previously reported neutralizing antibody. Surprisingly, we found that the receptor-binding site of this H5N1 hemagglutinin was already occupied by an α2-3-linked sialic acid and that this glycan emanated from asparagine N169 of a neighboring protomer on hemagglutinin itself. This structure thus highlights recognition by influenza hemagglutinin of an “auto”-α2-3-linked sialic acid from N169, an N-linked glycan conserved in 95% of H5 strains, and adds “auto-glycan recognition,” which may play a role in viral dispersal, to the complexities surrounding H5N1 zoonosis.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"31 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055152","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}

引用次数: 0

Computational design and improvement of a broad influenza virus HA stem targeting antibody

IF 5.7 2区生物学

Structure Pub Date : 2025-01-29 DOI: 10.1016/j.str.2025.01.002

Huarui Duan, Xiaojing Chi, Xuehua Yang, Shengnan Pan, Xiuying Liu, Peixiang Gao, Fangyuan Zhang, Xinhui Zhang, Xuemeng Dong, Yi Liao, Wei Yang

{"title":"Computational design and improvement of a broad influenza virus HA stem targeting antibody","authors":"Huarui Duan, Xiaojing Chi, Xuehua Yang, Shengnan Pan, Xiuying Liu, Peixiang Gao, Fangyuan Zhang, Xinhui Zhang, Xuemeng Dong, Yi Liao, Wei Yang","doi":"10.1016/j.str.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.01.002","url":null,"abstract":"Broadly neutralizing antibodies (nAbs) are vital therapeutic tools to counteract both pandemic and seasonal influenza threats. Traditional strategies for optimizing nAbs generally rely on labor-intensive, high-throughput mutagenesis screens. Here, we present an innovative structure-based design framework for the optimization of nAbs, which integrates epitope-paratope analysis, computational modeling, and rational design approaches, complemented by comprehensive experimental assessment. This approach was applied to optimize MEDI8852, a nAb targeting the stalk region of influenza A virus hemagglutinin (HA). The resulting variant, M18.1.2.2, shows a marked enhancement in both affinity and neutralizing efficacy, as demonstrated both in vitro and in vivo. Computational modeling reveals that this improvement can be attributed to the fine-tuning of interactions between the antibody’s side-chains and the epitope residues that are highly conserved across the influenza A virus HA stalk. Our dry-wet iterative protocol for nAb optimization presented here yielded a promising candidate for influenza intervention.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"112 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055387","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}

引用次数: 0

Structural insights into polyisoprenyl-binding glycosyltransferases

IF 5.7 2区生物学

Structure Pub Date : 2025-01-29 DOI: 10.1016/j.str.2025.01.003

Allen P. Zinkle, Ryan T. Morgan, Rie Nygaard, Filippo Mancia

引用次数: 0

Structural and functional analysis of SAM-dependent N-methyltransferases involved in ovoselenol and ovothiol biosynthesis

IF 5.7 2区生物学

Structure Pub Date : 2025-01-24 DOI: 10.1016/j.str.2024.12.020

Kendra A. Ireland, Chase M. Kayrouz, Marissa L. Abbott, Mohammad R. Seyedsayamdost, Katherine M. Davis

{"title":"Structural and functional analysis of SAM-dependent N-methyltransferases involved in ovoselenol and ovothiol biosynthesis","authors":"Kendra A. Ireland, Chase M. Kayrouz, Marissa L. Abbott, Mohammad R. Seyedsayamdost, Katherine M. Davis","doi":"10.1016/j.str.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.str.2024.12.020","url":null,"abstract":"Thio/selenoimidazole Nπ-methyltransferases are an emerging family of enzymes catalyzing the final step in the production of the S/Se-containing histidine-derived antioxidants ovothiol and ovoselenol. These enzymes, prevalent in prokaryotes, show minimal sequence similarity to other methyltransferases, and the structural determinants of their reactivities remain poorly understood. Herein, we report ligand-bound crystal structures of OvsM from the ovoselenol pathway as well as a member of a previously unknown clade of standalone ovothiol-biosynthetic Nπ-methyltransferases, which we have designated OvoM. Unlike previously reported ovothiol methyltransferases, which are fused as a C-terminal domain to the sulfoxide synthase OvoA, OvoMs function independently. Comparative structural analyses reveal conserved, ligand-induced conformational changes, suggesting similar behavior in dual-domain OvoA enzymes. Mutagenesis supports a model where OvoA domain rearrangement facilitates substrate recognition via a critical Tyr residue in the domain linker. Biochemical studies identify an essential active-site Asp, likely serving as a catalytic base in the SN2-like nucleophilic substitution reaction.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"13 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026723","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}

引用次数: 0