Nature structural & molecular biology最新文献_第5页

Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families 结构相关的TMC、TMEM16和TMEM63家族中离子通道和脂质重组酶的广泛细胞功能

Nature structural & molecular biology Pub Date : 2024-12-23 DOI: 10.1038/s41594-024-01444-x

Lily Yeh Jan, Yuh Nung Jan

{"title":"Wide-ranging cellular functions of ion channels and lipid scramblases in the structurally related TMC, TMEM16 and TMEM63 families","authors":"Lily Yeh Jan, Yuh Nung Jan","doi":"10.1038/s41594-024-01444-x","DOIUrl":"https://doi.org/10.1038/s41594-024-01444-x","url":null,"abstract":"Calcium (Ca2+)-activated ion channels and lipid scramblases in the transmembrane protein 16 (TMEM16) family are structurally related to mechanosensitive ion channels in the TMEM63 and transmembrane channel-like (TMC) families. Members of this structurally related superfamily share similarities in gating transitions and serve a wide range of physiological functions, which is evident from their disease associations. The TMEM16, TMEM63 and TMC families include members with important functions in the cell membrane and/or intracellular organelles such as the endoplasmic reticulum, membrane contact sites, endosomes and lysosomes. Moreover, some members of the TMEM16 family and the TMC family perform dual functions of ion channel and lipid scramblase, leading to intriguing physiological implications. In addition to their physiological functions such as mediating phosphatidylserine exposure and facilitation of extracellular vesicle generation and cell fusion, scramblases are involved in the entry and replication of enveloped viruses. Comparisons of structurally diverse scramblases may uncover features in the lipid-scrambling mechanisms that are likely shared by scramblases.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142874436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues 小鼠胚胎组织三维基因组和表观基因组的整合分析

Nature structural & molecular biology Pub Date : 2024-12-16 DOI: 10.1038/s41594-024-01431-2

Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren

{"title":"Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues","authors":"Miao Yu, Nathan R. Zemke, Ziyin Chen, Ivan Juric, Rong Hu, Ramya Raviram, Armen Abnousi, Rongxin Fang, Yanxiao Zhang, David U. Gorkin, Yang E. Li, Yuan Zhao, Lindsay Lee, Shreya Mishra, Anthony D. Schmitt, Yunjiang Qiu, Diane E. Dickel, Axel Visel, Len A. Pennacchio, Ming Hu, Bing Ren","doi":"10.1038/s41594-024-01431-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01431-2","url":null,"abstract":"While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"253 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Visualizing antibiotic action in a pathogenic bacterium at atomic to cellular scale 从原子到细胞尺度观察致病菌中的抗生素作用

Nature structural & molecular biology Pub Date : 2024-12-12 DOI: 10.1038/s41594-024-01442-z

引用次数: 0

Structural insights into context-dependent inhibitory mechanisms of chloramphenicol in cells 细胞中环境依赖性氯霉素抑制机制的结构见解

Nature structural & molecular biology Pub Date : 2024-12-12 DOI: 10.1038/s41594-024-01441-0

Liang Xue, Christian M. T. Spahn, Magdalena Schacherl, Julia Mahamid

{"title":"Structural insights into context-dependent inhibitory mechanisms of chloramphenicol in cells","authors":"Liang Xue, Christian M. T. Spahn, Magdalena Schacherl, Julia Mahamid","doi":"10.1038/s41594-024-01441-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01441-0","url":null,"abstract":"Ribosome-targeting antibiotics represent an important class of antimicrobial drugs. Chloramphenicol (Cm) is a well-studied ribosomal peptidyl transferase center (PTC) binder and growing evidence suggests that its inhibitory action depends on the sequence of the nascent peptide. How such selective inhibition on the molecular scale manifests on the cellular level remains unclear. Here, we use cryo-electron tomography to analyze the impact of Cm inside the bacterium Mycoplasma pneumoniae. By resolving the Cm-bound ribosomes to 3.0 Å, we elucidate Cm’s coordination with natural nascent peptides and transfer RNAs in the PTC. We find that Cm leads to the accumulation of a number of translation elongation states, indicating ongoing futile accommodation cycles, and to extensive ribosome collisions. We, thus, suggest that, beyond its direct inhibition of protein synthesis, the action of Cm may involve the activation of cellular stress responses. This work exemplifies how in-cell structural biology can expand the understanding of mechanisms of action for extensively studied antibiotics.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 of human γ-secretase inhibition by anticancer clinical compounds 抗癌临床化合物抑制人γ-分泌酶的结构基础

Nature structural & molecular biology Pub Date : 2024-12-09 DOI: 10.1038/s41594-024-01439-8

Xuefei Guo, Haotian Li, Xiaoli Lu, Hao Liu, Kaicheng U, Chuangye Yan, Jianlin Lei, Jing Huang, Rui Zhou, Yigong Shi

引用次数: 0

Substrate translocation and inhibition in human dicarboxylate transporter NaDC3 人二羧酸转运体NaDC3的底物易位和抑制作用

Nature structural & molecular biology Pub Date : 2024-12-02 DOI: 10.1038/s41594-024-01433-0

Yan Li, Jinmei Song, Vedrana Mikusevic, Jennifer J. Marden, Alissa Becerril, Huihui Kuang, Bing Wang, William J. Rice, Joseph A. Mindell, Da-Neng Wang

{"title":"Substrate translocation and inhibition in human dicarboxylate transporter NaDC3","authors":"Yan Li, Jinmei Song, Vedrana Mikusevic, Jennifer J. Marden, Alissa Becerril, Huihui Kuang, Bing Wang, William J. Rice, Joseph A. Mindell, Da-Neng Wang","doi":"10.1038/s41594-024-01433-0","DOIUrl":"https://doi.org/10.1038/s41594-024-01433-0","url":null,"abstract":"The human high-affinity sodium–dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling molecules. Understanding the cellular signaling process and developing inhibitors require knowledge of the structural basis of the dicarboxylate specificity and inhibition mechanism of NaDC3. To this end, we determined the cryo-electron microscopy structures of NaDC3 in various dimers, revealing the protomer in three conformations: outward-open Co, outward-occluded Coo and inward-open Ci. A dicarboxylate is first bound and recognized in Co and how the substrate interacts with NaDC3 in Coo likely helps to further determine the substrate specificity. A phenylalanine from the scaffold domain interacts with the bound dicarboxylate in the Coo state and modulates the kinetic barrier to the transport domain movement. Structural comparison of an inhibitor-bound structure of NaDC3 to that of the sodium-dependent citrate transporter suggests ways for making an inhibitor that is specific for NaDC3.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"204 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The yeast genome is globally accessible in living cells 酵母基因组可在活细胞中全球访问

Nature structural & molecular biology Pub Date : 2024-11-25 DOI: 10.1038/s41594-024-01318-2

Hemant K. Prajapati, Peter R. Eriksson, Paul A. Elizalde, Christopher T. Coey, Zhuwei Xu, David J. Clark

{"title":"The yeast genome is globally accessible in living cells","authors":"Hemant K. Prajapati, Peter R. Eriksson, Paul A. Elizalde, Christopher T. Coey, Zhuwei Xu, David J. Clark","doi":"10.1038/s41594-024-01318-2","DOIUrl":"https://doi.org/10.1038/s41594-024-01318-2","url":null,"abstract":"Eukaryotic genomes are packaged into chromatin, which is composed of condensed filaments of regularly spaced nucleosomes, resembling beads on a string. The nucleosome contains ~147 bp of DNA wrapped almost twice around a central core histone octamer. The packaging of DNA into chromatin represents a challenge to transcription factors and other proteins requiring access to their binding sites. Consequently, control of DNA accessibility is thought to play a key role in gene regulation. Here we measure DNA accessibility genome wide in living budding yeast cells by inducible expression of DNA methyltransferases. We find that the genome is globally accessible in living cells, unlike in isolated nuclei, where DNA accessibility is severely restricted. Gene bodies are methylated at only slightly slower rates than promoters, indicating that yeast chromatin is highly dynamic in vivo. In contrast, silenced loci and centromeres are strongly protected. Global shifts in nucleosome positions occur in cells as they are depleted of ATP-dependent chromatin remodelers, suggesting that nucleosome dynamics result from competition among these enzymes. We conclude that chromatin is in a state of continuous flux in living cells, but static in nuclei, suggesting that DNA packaging in yeast is not generally repressive.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Na+-V-ATPase inhibitor curbs VRE growth and unveils Na+ pathway structure Na+-V-ATP酶抑制剂抑制VRE生长并揭示Na+通路结构

Nature structural & molecular biology Pub Date : 2024-11-21 DOI: 10.1038/s41594-024-01419-y

Kano Suzuki, Yoshiyuki Goto, Akihiro Otomo, Kouki Shimizu, Shohei Abe, Katsuhiko Moriyama, Satoshi Yasuda, Yusuke Hashimoto, Jun Kurushima, Sho Mikuriya, Fabiana L. Imai, Naruhiko Adachi, Masato Kawasaki, Yumi Sato, Satoshi Ogasawara, So Iwata, Toshiya Senda, Mitsunori Ikeguchi, Haruyoshi Tomita, Ryota Iino, Toshio Moriya, Takeshi Murata

{"title":"Na+-V-ATPase inhibitor curbs VRE growth and unveils Na+ pathway structure","authors":"Kano Suzuki, Yoshiyuki Goto, Akihiro Otomo, Kouki Shimizu, Shohei Abe, Katsuhiko Moriyama, Satoshi Yasuda, Yusuke Hashimoto, Jun Kurushima, Sho Mikuriya, Fabiana L. Imai, Naruhiko Adachi, Masato Kawasaki, Yumi Sato, Satoshi Ogasawara, So Iwata, Toshiya Senda, Mitsunori Ikeguchi, Haruyoshi Tomita, Ryota Iino, Toshio Moriya, Takeshi Murata","doi":"10.1038/s41594-024-01419-y","DOIUrl":"https://doi.org/10.1038/s41594-024-01419-y","url":null,"abstract":"Vancomycin-resistant Enterococcus faecium (VRE) is a major cause of nosocomial infections, particularly endocarditis and sepsis. With the diminishing effectiveness of antibiotics against VRE, new antimicrobial agents are urgently needed. Our previous research demonstrated the crucial role of Na+-transporting V-ATPase in Enterococcus hirae for growth under alkaline conditions. In this study, we identified a compound, V-161, from 70,600 compounds, which markedly inhibits E. hirae V-ATPase activity. V-161 not only inhibits VRE growth in alkaline conditions but also significantly suppresses VRE colonization in the mouse small intestine. Furthermore, we unveiled the high-resolution structure of the membrane VO part due to V-161 binding. V-161 binds to the interface of the c-ring and a-subunit, constituting the Na+ transport pathway in the membrane, thereby halting its rotation. This structural insight presents potential avenues for developing therapeutic agents for VRE treatment and elucidates the Na+ transport pathway and mechanism.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"180 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Architecture and activation of single-pass transmembrane receptor guanylyl cyclase 单通道跨膜受体鸟苷酸环化酶的结构与激活

Nature structural & molecular biology Pub Date : 2024-11-14 DOI: 10.1038/s41594-024-01426-z

Shian Liu, Alexander M. Payne, Jinan Wang, Lan Zhu, Navid Paknejad, Edward T. Eng, Wei Liu, Yinglong Miao, Richard K. Hite, Xin-Yun Huang

{"title":"Architecture and activation of single-pass transmembrane receptor guanylyl cyclase","authors":"Shian Liu, Alexander M. Payne, Jinan Wang, Lan Zhu, Navid Paknejad, Edward T. Eng, Wei Liu, Yinglong Miao, Richard K. Hite, Xin-Yun Huang","doi":"10.1038/s41594-024-01426-z","DOIUrl":"https://doi.org/10.1038/s41594-024-01426-z","url":null,"abstract":"The heart, in addition to its primary role in blood circulation, functions as an endocrine organ by producing cardiac hormone natriuretic peptides. These hormones regulate blood pressure through the single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor 1. The binding of the peptide hormones to the extracellular domain of the receptor activates the intracellular guanylyl cyclase domain of the receptor to produce the second messenger cyclic guanosine monophosphate. Despite their importance, the detailed architecture and domain interactions within full-length GC-A remain elusive. Here we present cryo-electron microscopy structures, functional analyses and molecular dynamics simulations of full-length human GC-A, in both the absence and the presence of atrial natriuretic peptide. The data reveal the architecture of full-length GC-A, highlighting the spatial arrangement of its various functional domains. This insight is crucial for understanding how different parts of the receptor interact and coordinate during activation. The study elucidates the molecular basis of how extracellular signals are transduced across the membrane to activate the intracellular guanylyl cyclase domain.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 the yeast ceramide synthase 酵母神经酰胺合成酶的结构

Nature structural & molecular biology Pub Date : 2024-11-11 DOI: 10.1038/s41594-024-01415-2

Jan-Hannes Schäfer, Lena Clausmeyer, Carolin Körner, Bianca M. Esch, Verena N. Wolf, Jennifer Sapia, Yara Ahmed, Stefan Walter, Stefano Vanni, Dovile Januliene, Arne Moeller, Florian Fröhlich

引用次数: 0