IF 5.7 2区生物学

Structure Pub Date : 2025-06-18 DOI: 10.1016/j.str.2025.05.015

Victoria Castro, Gema Calvo, Ana J. Pérez-Berná, Kevin Mamprin, Sergey Kapishnikov, David Rogers, Stephen O'Connor, Paul Sheridan, Kenneth Fahy, Eva Pereiro, Pablo Gastaminza

{"title":"Rapid hepatitis C virus replication machinery removal after antiviral treatment with DAA monitored by multimodal imaging","authors":"Victoria Castro, Gema Calvo, Ana J. Pérez-Berná, Kevin Mamprin, Sergey Kapishnikov, David Rogers, Stephen O'Connor, Paul Sheridan, Kenneth Fahy, Eva Pereiro, Pablo Gastaminza","doi":"10.1016/j.str.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.str.2025.05.015","url":null,"abstract":"Hepatitis C virus (HCV) replication causes a profound remodeling of the host endomembrane system. The availability of direct-acting antiviral (DAA) drugs provides an opportunity to define the ultrastructural events that follow viral replication blockade using confocal immunofluorescence, transmission electron microscopy (TEM) as well as correlative cryogenic light-soft X-ray tomography (CLSXT). Study of DAA-treated HCV replicons using CLSXT indicates that HCV-induced membranous alterations are no longer visible after 24 h of treatment and that a component of the replicase is located in pleomorphic, high-absorption contrast acidic organelles. TEM studies confirmed the rapid elimination of the viral machinery, and the concurrent appearance of large endo-lysosomes in DAA-treated cells. These and results by others suggest that HCV replication compartment may constantly be recycled by the endo-lysosomal system and that this equilibrium is unbalanced by DAA treatment, resulting in a transient activation of the endo-lysosomal system to achieve rapid viral machinery removal.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"12 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311687","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

High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1 高通量低温电镜为溶酶体离子通道TRPML1的调节剂提供了结构理解

IF 5.7 2区生物学

Structure Pub Date : 2025-06-17 DOI: 10.1016/j.str.2025.05.014

Judith Reeks, Pravin Mahajan, Mellissa Clark, Suzanna R. Cowan, Elena Di Daniel, Christopher P. Earl, Samantha Fisher, Rhian S. Holvey, Scott M. Jackson, Emyr Lloyd-Evans, Carmine M. Morgillo, Paul N. Mortenson, Marc O’Reilly, Caroline J. Richardson, Patrick Schöpf, Daniel M. Tams, Helen Waller-Evans, Simon E. Ward, Stuart Whibley, Pamela A. Williams, Christopher N. Johnson

{"title":"High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1","authors":"Judith Reeks, Pravin Mahajan, Mellissa Clark, Suzanna R. Cowan, Elena Di Daniel, Christopher P. Earl, Samantha Fisher, Rhian S. Holvey, Scott M. Jackson, Emyr Lloyd-Evans, Carmine M. Morgillo, Paul N. Mortenson, Marc O’Reilly, Caroline J. Richardson, Patrick Schöpf, Daniel M. Tams, Helen Waller-Evans, Simon E. Ward, Stuart Whibley, Pamela A. Williams, Christopher N. Johnson","doi":"10.1016/j.str.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.str.2025.05.014","url":null,"abstract":"Access to high-resolution structural data for protein-ligand complexes is a prerequisite for structure-based medicinal chemistry, where the ability to iterate cycles of design-structure-redesign is highly desirable. For proteins refractory to X-ray crystallography, such as integral membrane proteins, enablement of high throughput structure determination by cryoelectron microscopy (cryo-EM) has the potential to be transformational for structure-based design. We have applied such an approach to the lysosomal ion channel transient receptor potential mucolipin 1 (TRPML1) in complex with ten chemically diverse modulators, both agonists and antagonists. The resulting depth of high-resolution structural data generated provides important insights into protein-ligand structure-function relationships, including mechanistic understanding of ligand-induced channel pore opening and closing. Moreover, the knowledge gained has the potential to support iterative design cycles toward improved modulators of this important biological target.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"11 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305466","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 continuous evolution of biomolecular force fields 生物分子力场的不断演化

IF 5.7 2区生物学

Structure Pub Date : 2025-06-16 DOI: 10.1016/j.str.2025.05.013

Xiaoli Lu, Jinfeng Chen, Jing Huang

引用次数: 0

A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain III类配体在内部和末端结合模式之间振荡，因为它与散乱PDZ结构域接合

IF 5.7 2区生物学

Structure Pub Date : 2025-06-13 DOI: 10.1016/j.str.2025.05.012

Jitender Kumar, Miroslav Micka, Jan Komárek, Tomáš Klumpler, Vojtěch Bystrý, Remco Sprangers, Cyril Bařinka, Vítězslav Bryja, Konstantinos Tripsianes

{"title":"A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain","authors":"Jitender Kumar, Miroslav Micka, Jan Komárek, Tomáš Klumpler, Vojtěch Bystrý, Remco Sprangers, Cyril Bařinka, Vítězslav Bryja, Konstantinos Tripsianes","doi":"10.1016/j.str.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.str.2025.05.012","url":null,"abstract":"One of the largest domain-motif interactomes in human involves PSD-95/Discs-large/ZO-1 (PDZ) domains. The framework for understanding the PDZ interactome is well established; however the functional dynamics associated with PDZ-ligand interactions are poorly understood. Here, we report a dual PDZ-binding mode that ascribes unique dynamic features to class III ligand recognition. The crystal structure revealed that the PDZ domain can recognize either of the carboxylate moieties (terminal or internal) present in the class III ligand and laid out the register rules responsible for the dual recognition. Variants of the ligand designed to retain one or the other carboxylate of the native sequence were sufficient for PDZ binding. The conformational dynamics of PDZ probed by NMR relaxation dispersion experiments demonstrated that the class III ligand is shuffling binding modes as it engages with the PDZ domain. Our mechanistic findings reveal yet another aspect of PDZ binding plasticity specific to class III ligands.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"26 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278667","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

Redefining the role of the EryM acetyltransferase in natural product biosynthetic pathways 重新定义EryM乙酰转移酶在天然产物生物合成途径中的作用

IF 5.7 2区生物学

Structure Pub Date : 2025-06-13 DOI: 10.1016/j.str.2025.05.011

Yihua Li, Xunkun Liu, Natalia R. Harris, Jacquelyn R. Roberts, Estefanía Martínez Valdivia, Xinrui Ji, Janet L. Smith

{"title":"Redefining the role of the EryM acetyltransferase in natural product biosynthetic pathways","authors":"Yihua Li, Xunkun Liu, Natalia R. Harris, Jacquelyn R. Roberts, Estefanía Martínez Valdivia, Xinrui Ji, Janet L. Smith","doi":"10.1016/j.str.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.05.011","url":null,"abstract":"The GNAT (GCN5-related N-acetyltransferase) superfamily comprises enzymes with a conserved fold and diverse catalytic activities, including primarily acyl transfer, with a few examples of decarboxylation. EryM, a GNAT from Saccharopolyspora erythraea, has been implicated in both erythromycin and erythrochelin biosynthesis, with dual functionality as an acetyltransferase and a decarboxylase. Despite an historical association with malonyl-coenzyme A decarboxylation activity, this dual activity has remained enigmatic as its close homologs were identified with only acyl transfer activity. Here, functional assays demonstrate that EryM catalyzes acyl transfer but lacks decarboxylation activity, challenging long-standing assumptions about its biosynthetic role. Crystal structures of EryM and an acetyl-CoA complex and comparison with homologs in siderophore pathways reveal a conserved catalytic pocket with an essential His and identically positioned side chains common to GNAT enzymes for N-acyl transfer from CoA to primary hydroxylamine substrates. Bioinformatic analysis defines a large GNAT subfamily broadly distributed in the microbial world.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"7 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278666","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 ZBTB20 action at the AFP promoter ZBTB20在AFP启动子上作用的结构见解

IF 5.7 2区生物学

Structure Pub Date : 2025-06-09 DOI: 10.1016/j.str.2025.05.009

Lingna Yang, Huajiao Xie, Xiaoqing Wan, Mengfeng Li, Mengqi Lv, Yi Duan, Yunyu Shi, Weiping J. Zhang, Fudong Li

引用次数: 0

Secondary chelation through shared water provides ion selectivity in bacterial sodium channels 通过共享水的二级螯合作用在细菌钠离子通道中提供离子选择性

IF 5.7 2区生物学

Structure Pub Date : 2025-06-09 DOI: 10.1016/j.str.2025.05.010

Yury A. Trofimov, Anton O. Chugunov, Alexander A. Vassilevski

{"title":"Secondary chelation through shared water provides ion selectivity in bacterial sodium channels","authors":"Yury A. Trofimov, Anton O. Chugunov, Alexander A. Vassilevski","doi":"10.1016/j.str.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.str.2025.05.010","url":null,"abstract":"Selective ion conductance through sodium channels has been intensely investigated for decades. Here, we focus on the sodium and potassium hydration shell structure and propose the mechanism of Na+ over K+ selectivity in the bacterial sodium channel NavMs. We suggest that the channel selectivity filter forms hydrogen bonds with Na+ hydration shell in a perfect octahedral stereometry, which mimics bulk water and provides high Na+ conductance. Using molecular dynamics simulations, we reveal a conserved ion-binding site formed by carboxyl/carbonyl groups, where both Na+ and K+ remain fully hydrated. While passing through the selectivity filter, Na+ octahedral shell remains unhindered, while K+ square antiprismatic shell is squeezed, creating an energy barrier for K+ current. In contrast to K+-channels, where the selectivity filter interacts with the permeating ions directly (“primary” chelation), NavMs gropes the ion hydration shell, performing “secondary” chelation. This ion recognition mechanism is probably widespread in other channels and pores.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"7 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237991","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 plasticity of bacterial ubiquitin-like proteins in stress sensing 细菌泛素样蛋白在应激感知中的结构可塑性

IF 5.7 2区生物学

Structure Pub Date : 2025-06-05 DOI: 10.1016/j.str.2025.05.002

Weixun Li, Xiang Gao

引用次数: 0

Color mapping of multitarget protein clusters 多靶点蛋白簇的颜色映射

IF 5.7 2区生物学

Structure Pub Date : 2025-06-05 DOI: 10.1016/j.str.2025.05.004

Hirushi Gunasekara, Ying S. Hu

引用次数: 0

Antimalarial drug artemisinin stabilizes PfRACK1 binding to the ribosome 抗疟药物青蒿素稳定PfRACK1与核糖体的结合