PLoS Biology最新文献_第7页

Membrane asymmetry facilitates murine norovirus entry and persistent enteric infection. 膜不对称有利于小鼠诺如病毒进入和持续的肠道感染。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003147

Brittany M Stewart, Linley R Pierce, Mikayla C Olson, Chengyuan Ji, Robert C Orchard

{"title":"Membrane asymmetry facilitates murine norovirus entry and persistent enteric infection.","authors":"Brittany M Stewart, Linley R Pierce, Mikayla C Olson, Chengyuan Ji, Robert C Orchard","doi":"10.1371/journal.pbio.3003147","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003147","url":null,"abstract":"Norovirus, the leading cause of gastroenteritis worldwide, is a non-enveloped virus whose tropism is determined in part by the expression patterns of entry receptors. However, the contribution of cellular lipids to viral entry is not well understood. Here, we determined that the asymmetrical distribution of lipids within membrane bilayers is required for murine norovirus (MNV) replication. Specifically, TMEM30a, an essential subunit of lipid flippases, is required for MNV replication in vitro. Disruption of TMEM30a in mouse intestinal epithelial cells prevents persistent, enteric infection by MNV in vivo. Mechanistically, TMEM30a facilitates MNV binding and entry. Surprisingly, exoplasmic phosphatidylserine (PS), a typical marker of dying cells, does not inhibit MNV infection. Rather, TMEM30a maintains a lipid-ordered state that impacts membrane fluidity that is necessary for the low affinity, high avidity binding of MNV to cells. Our data provides a new role for lipid asymmetry in promoting non-enveloped virus infection in vitro and norovirus persistence in vivo.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003147"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cross-species analysis of the nuclease Artemis highlights its evolving function in domesticating RAG-like transposons and residues that are crucial for activity. 对核酸酶Artemis的跨物种分析强调了其在驯化rag样转座子和残基方面的进化功能，这些转座子和残基对活性至关重要。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003056

Ziwen Huang, Zhenxi Cai, Xin Tao, Xinli Wang, Xiaoxue Tian, Fan Chen, Zhen Li, Anlong Xu, Shaochun Yuan

{"title":"Cross-species analysis of the nuclease Artemis highlights its evolving function in domesticating RAG-like transposons and residues that are crucial for activity.","authors":"Ziwen Huang, Zhenxi Cai, Xin Tao, Xinli Wang, Xiaoxue Tian, Fan Chen, Zhen Li, Anlong Xu, Shaochun Yuan","doi":"10.1371/journal.pbio.3003056","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003056","url":null,"abstract":"The discovery of the ProtoRAG transposon in lancelets revealed that V(D)J recombination originates from the Recombination activating gene-like (RAGL) transposon. Analogous to the vertebrate RAG complex, the RAGL transposase nicks host flanking DNA and leads to the formation of hairpin ends. Here, we showed that the Artemis nuclease, which is capable of resolving DNA hairpin ends generated during V(D)J recombination, is also responsible for unraveling ProtoRAG-mediated DNA hairpin ends. Notably, like the RAGL transposon, Artemis originated from the eukaryotic common ancestor. By tracing the evolving function of Artemis from cephalochordates to vertebrates, we revealed the lineage specific allele polymorphism of lancelet Artemis and uncovered an increased activity on hairpin DNA opening in vertebrate Artemis. Additionally, the evolutionarily conserved LYCS motif in Artemis β6, which may be associated with disease, is demonstrated to be crucial for its function. Overall, this study highlights the evolving function of Artemis, identifies novel critical residues, and provides new insights into the evolution of RAG-mediated recombination and the clinical therapy of Artemis deficient disease.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003056"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 length of the G1 phase is an essential determinant of H3K27me3 landscapes across diverse cell types. G1期的长度是H3K27me3在不同细胞类型中的基本决定因素。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003119

Abby Trouth, Kameswaran Ravichandran, Philip R Gafken, Sara Martire, Gabriel E Boyle, Giovana M B Veronezi, Van La, Stephanie J Namciu, Laura A Banaszynski, Jay F Sarthy, Srinivas Ramachandran

{"title":"The length of the G1 phase is an essential determinant of H3K27me3 landscapes across diverse cell types.","authors":"Abby Trouth, Kameswaran Ravichandran, Philip R Gafken, Sara Martire, Gabriel E Boyle, Giovana M B Veronezi, Van La, Stephanie J Namciu, Laura A Banaszynski, Jay F Sarthy, Srinivas Ramachandran","doi":"10.1371/journal.pbio.3003119","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003119","url":null,"abstract":"Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted 2-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a short G1 phase restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mouse embryonic stem cells (mESCs) globally and at specific loci upon G1 phase lengthening - accomplished by thymidine block or growth in the absence of serum (with the \"2i medium\"). H3K27me3 levels in mESCs increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of G1 length as a critical regulator of the stem cell epigenome. Furthermore, we demonstrate the inverse effect - that G1 shortening in differentiated human HEK293 cells results in a loss of H3K27me3 levels. Finally, in human tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003119"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuronal responses in the human primary motor cortex coincide with the subjective onset of movement intention in brain-machine interface-mediated actions. 在脑机界面介导的动作中，人类初级运动皮层的神经元反应与运动意图的主观发生一致。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003118

Jean-Paul Noel, Marcie Bockbrader, Tommaso Bertoni, Sam Colachis, Marco Solca, Pavo Orepic, Patrick D Ganzer, Patrick Haggard, Ali Rezai, Olaf Blanke, Andrea Serino

{"title":"Neuronal responses in the human primary motor cortex coincide with the subjective onset of movement intention in brain-machine interface-mediated actions.","authors":"Jean-Paul Noel, Marcie Bockbrader, Tommaso Bertoni, Sam Colachis, Marco Solca, Pavo Orepic, Patrick D Ganzer, Patrick Haggard, Ali Rezai, Olaf Blanke, Andrea Serino","doi":"10.1371/journal.pbio.3003118","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003118","url":null,"abstract":"Self-initiated behavior is accompanied by the experience of intending our actions. Here, we leverage the unique opportunity to examine the full intentional chain-from intention to action to environmental effects-in a tetraplegic person outfitted with a primary motor cortex (M1) brain-machine interface (BMI) generating real hand movements via neuromuscular electrical stimulation (NMES). This combined BMI-NMES approach allowed us to selectively manipulate each element of the intentional chain (intention, action, effect) while probing subjective experience and performing extra-cellular recordings in human M1. Behaviorally, we reveal a novel form of intentional binding: motor intentions are reflected in a perceived temporal attraction between the onset of intentions and that of actions. Neurally, we demonstrate that evoked spiking activity in M1 largely coincides in time with the onset of the experience of intention and that M1 spike counts and the onset of subjective intention may co-vary on a trial-by-trial basis. Further, population-level dynamics, as indexed by a decoder instantiating movement, reflect intention-action temporal binding. The results fill a significant knowledge gap by relating human spiking activity in M1 with the onset of subjective intention and complement prior human intracranial work examining pre-motor and parietal areas.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003118"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Membrane-associated σ factors disrupt rRNA operon clustering in Escherichia coli. 膜相关σ因子在大肠杆菌中破坏rRNA操纵子聚集。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003113

Khang Ho, Rasika M Harshey

{"title":"Membrane-associated σ factors disrupt rRNA operon clustering in Escherichia coli.","authors":"Khang Ho, Rasika M Harshey","doi":"10.1371/journal.pbio.3003113","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003113","url":null,"abstract":"Chromosomal organization in Escherichia coli as examined by Hi-C methodology indicates that long-range interactions are sparse. Yet, spatial co-localization or \"clustering\" of 6/7 ribosomal RNA (rrn) operons distributed over half the 4.6 Mbp genome has been captured by two other methodologies-fluorescence microscopy and Mu transposition. Our current understanding of the mechanism of clustering is limited to mapping essential cis elements. To identify trans elements, we resorted to perturbing the system by chemical and physical means and observed that heat shock disrupts clustering. Levels of σH are known to rise as a cellular response to the shock. We show that elevated expression of σH alone is sufficient to disrupt clustering, independent of heat stress. The anti-clustering activity of σH does not depend on its transcriptional activity but requires core-RNAP interaction and DNA-binding activities. This activity of σH is suppressed by ectopic expression of σD suggesting a competition for core-RNAP. A query of the other five known σ factors of E. coli found that elevated expression of FecI, the ECF σ factor that controls iron citrate transport, also perturbs clustering and is also suppressed by σD. We discuss a possible scenario for how these membrane-associated σ factors participate in clustering of distant rrn loci.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003113"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure of the scaffolding protein and portal within the bacteriophage P22 procapsid provides insights into the self-assembly process. 噬菌体P22原衣壳内的支架蛋白和入口的结构提供了对自组装过程的见解。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-17 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003104

Hao Xiao, Wenyuan Chen, Hao Pang, Jing Zheng, Li Wang, Hao Feng, Jingdong Song, Lingpeng Cheng, Hongrong Liu

{"title":"Structure of the scaffolding protein and portal within the bacteriophage P22 procapsid provides insights into the self-assembly process.","authors":"Hao Xiao, Wenyuan Chen, Hao Pang, Jing Zheng, Li Wang, Hao Feng, Jingdong Song, Lingpeng Cheng, Hongrong Liu","doi":"10.1371/journal.pbio.3003104","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003104","url":null,"abstract":"In the assembly pathway of tailed double-stranded DNA (dsDNA) bacteriophages and herpesviruses, a procapsid with a dodecameric portal for DNA delivery at a unique vertex is initially formed. Appropriate procapsid assembly requires the transient presence of multiple copies of a scaffolding protein (SP), which is absent in the mature virion. However, how the SP contributes to dodecameric portal formation, facilitates portal and coat protein incorporation, and is subsequently released remains unclear because of a lack of structural information. Here, we present the structure of the SP-portal complex within the procapsid of bacteriophage P22 at 3-9 Å resolutions. The AlphaFold2-predicted SP model fits well with the density map of the complex. The SP forms trimers and tetramers that interact to yield a dome-like complex on the portal. Two SP domains mediate multimerization. Each trimer interacts with two neighboring portal subunits. The SP has a loop-hook-like structure that aids in coat protein recruitment during viral assembly. The loops of those SP subunits on the portal are positioned in clefts between adjacent portal subunits. Conformational changes in the portal during phage maturation may trigger the disassembly and release of the SP complex. Our findings provide insights into SP-assisted procapsid assembly in bacteriophage P22 and suggest that this strategy is also implemented by other dsDNA viruses, including herpesviruses.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003104"},"PeriodicalIF":9.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Applications and status of gene drive in plants. 基因驱动技术在植物中的应用及现状。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-15 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003148

Bruce A Hay

引用次数: 0

Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination. 单核细胞分泌的Wnt降低了中枢神经系统髓鞘再生的效率。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-15 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003073

Bianca M Hill, Rebecca K Holloway, Lindsey H Forbes, Claire L Davies, Jonathan K Monteiro, Christina M Brown, Jamie Rose, Neva Fudge, Pamela J Plant, Ayisha Mahmood, Koroboshka Brand-Arzamendi, Sarah A Kent, Irene Molina-Gonzalez, Stefka Gyoneva, Richard M Ransohoff, Brian Wipke, Josef Priller, Raphael Schneider, Craig S Moore, Veronique E Miron

{"title":"Monocyte-secreted Wnt reduces the efficiency of central nervous system remyelination.","authors":"Bianca M Hill, Rebecca K Holloway, Lindsey H Forbes, Claire L Davies, Jonathan K Monteiro, Christina M Brown, Jamie Rose, Neva Fudge, Pamela J Plant, Ayisha Mahmood, Koroboshka Brand-Arzamendi, Sarah A Kent, Irene Molina-Gonzalez, Stefka Gyoneva, Richard M Ransohoff, Brian Wipke, Josef Priller, Raphael Schneider, Craig S Moore, Veronique E Miron","doi":"10.1371/journal.pbio.3003073","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003073","url":null,"abstract":"The regeneration of myelin in the central nervous system (CNS) reinstates nerve health and function, yet its decreased efficiency with aging and progression of neurodegenerative disease contributes to axonal loss and/or degeneration. Although CNS myeloid cells have been implicated in regulating the efficiency of remyelination, the distinct contribution of blood monocytes versus that of resident microglia is unclear. Here, we reveal that monocytes have non-redundant functions compared to microglia in regulating remyelination. Using a transgenic mouse in which classical monocytes have reduced egress from bone marrow (Ccr2-/-), we demonstrate that monocytes drive the timely onset of oligodendrocyte differentiation and myelin protein expression, yet impede myelin production. Ribonucleic acid sequencing revealed a Wnt signature in wild-type mouse lesion monocytes, which was confirmed in monocytes from multiple sclerosis white matter lesions and blood. Genetic or pharmacological inhibition of Wnt release by monocytes increased remyelination. Our findings reveal monocytes to be critical regulators of remyelination and identify monocytic Wnt signaling as a promising therapeutic target to inhibit for increased efficiency of CNS regeneration.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003073"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12052099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

How did vocal communication come to dominate human language? A view from the womb. 声音交流是如何主宰人类语言的？子宫里的景色。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-15 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003141

Alexis Hervais-Adelman, Simon W Townsend

{"title":"How did vocal communication come to dominate human language? A view from the womb.","authors":"Alexis Hervais-Adelman, Simon W Townsend","doi":"10.1371/journal.pbio.3003141","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003141","url":null,"abstract":"Whether human language evolved via a gestural or a vocal route remains an unresolved and contentious issue. Given the existence of two preconditions-a \"language faculty\" and the capacity for imitative learning both vocally and manually-there is no compelling evidence for gesture being inherently inferior to vocalization as a mode of linguistic expression; indeed, signed languages are capable of the same expressive range as spoken ones. Here, we revisit this conundrum, championing recent methodological advances in human neuroimaging (specifically, in utero functional magnetic resonance imaging) as a window into the role of the prenatal gestational period in language evolution, a critical, yet currently underexplored environment in which fetuses are exposed to, and become attuned to, spoken language. In this Unsolved Mystery, we outline how, compared to visual sensitivity, the ontogenically earlier development of auditory sensitivity, beginning in utero and persisting for several months post-partum, alongside the relative permeability of the uterine environment to sound, but not light, may constitute a small but significant contribution to the current dominance of spoken language.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003141"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12021287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity. g蛋白偶联受体HCAR1与Gi1蛋白复合物的结构揭示了配体识别和激动剂选择性的机制基础。

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-04-15 eCollection Date: 2025-04-01 DOI: 10.1371/journal.pbio.3003126

Xin Pan, Fang Ye, Peiruo Ning, Yiping Yu, Zhiyi Zhang, Jingxuan Wang, Geng Chen, Zhangsong Wu, Chen Qiu, Jiancheng Li, Bangning Chen, Lizhe Zhu, Chungen Qian, Kaizheng Gong, Yang Du

{"title":"Structures of G-protein coupled receptor HCAR1 in complex with Gi1 protein reveal the mechanistic basis for ligand recognition and agonist selectivity.","authors":"Xin Pan, Fang Ye, Peiruo Ning, Yiping Yu, Zhiyi Zhang, Jingxuan Wang, Geng Chen, Zhangsong Wu, Chen Qiu, Jiancheng Li, Bangning Chen, Lizhe Zhu, Chungen Qian, Kaizheng Gong, Yang Du","doi":"10.1371/journal.pbio.3003126","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003126","url":null,"abstract":"Hydroxycarboxylic acid receptor 1 (HCAR1), also known as lactate receptor or GPR81, is a class A G-protein-coupled receptor with key roles in regulating lipid metabolism, neuroprotection, angiogenesis, cardiovascular function, and inflammatory response in humans. HCAR1 is highly expressed in numerous types of cancer cells, where it participates in controlling cancer cell metabolism and defense mechanisms, rendering it an appealing target for cancer therapy. However, the molecular basis of HCAR1-mediated signaling remains poorly understood. Here, we report four cryo-EM structures of human HCAR1 and HCAR2 in complex with the Gi1 protein, in which HCAR1 binds to the subtype-specific agonist CHBA (3.16 Å) and apo form (3.36 Å), and HCAR2 binds to the subtype-specific agonists MK-1903 (2.68 Å) and SCH900271 (3.06 Å). Combined with mutagenesis and cellular functional assays, we elucidate the mechanisms underlying ligand recognition, receptor activation, and G protein coupling of HCAR1. More importantly, the key residues that determine ligand selectivity between HCAR1 and HCAR2 are clarified. On this basis, we further summarize the structural features of agonists that match the orthosteric pockets of HCAR1 and HCAR2. These structural insights are anticipated to greatly accelerate the development of novel HCAR1-targeted drugs, offering a promising avenue for the treatment of various diseases.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003126"},"PeriodicalIF":9.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0