Nature chemical biology最新文献_第10页

Drugging endosomal flux 药物内体通量。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-10 DOI: 10.1038/s41589-026-02259-1

Francesco Peri, Francesca Fallarino

引用次数: 0

Protein stability is determined by single-site bias rather than pairwise covariance 蛋白质稳定性是由单位点偏倚而不是两两协方差决定的。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-10 DOI: 10.1038/s41589-026-02270-6

Matt Sternke, Katherine W. Tripp, Soumya Prakash Behera, Justin P. Nguyen, Doug Barrick

{"title":"Protein stability is determined by single-site bias rather than pairwise covariance","authors":"Matt Sternke, Katherine W. Tripp, Soumya Prakash Behera, Justin P. Nguyen, Doug Barrick","doi":"10.1038/s41589-026-02270-6","DOIUrl":"10.1038/s41589-026-02270-6","url":null,"abstract":"The biases revealed in protein sequence alignments have been shown to provide information related to protein structure, stability and function. Recent studies using Potts models show that single-site biases and pair correlations can improve predictions of protein fitness, activity and stability compared to simpler models. Here we use a Potts model to design groups of protein sequences with different amounts of single-site biases and pair correlations and determine the stabilities of sequences from each group. Surprisingly, sequences excluding pair correlations maximize stability compared to sequences that maximize pair correlations, suggesting that pair correlations contribute to other aspects of protein fitness. Consistent with this interpretation, we find that for three enzyme families, activity is greatly increased by maximizing pair correlations. The finding that elimination of covariant residue pairs increases protein stability suggests a route to enhance stability of designed proteins, although this stability may be offset by reduced enzyme activity. Sequence biases at individual positions can be used to design more stable protein variants, while correlation between pairs of residues has also been shown to be important for specifying protein structure and function. Here, a Potts model is used to separate the contributions of single-site biases and pair correlations, revealing that protein structure is stabilized by single-site biases rather than pairwise coupling, while pairwise coupling is important for protein function.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 8","pages":"1252-1261"},"PeriodicalIF":15.8,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41589-026-02270-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422787","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

Tumor immune cell targeting chimeras reprogram tumor-associated macrophages 肿瘤免疫细胞靶向嵌合体重编程肿瘤相关巨噬细胞

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-08 DOI: 10.1038/s41589-026-02258-2

Mariko Morimoto, David S. Roberts, Ru M. Wen, Ell Handy, Eric E. Peterson, Grace M. Stepek, Nicholas A. Till, James D. Brooks, Carolyn R. Bertozzi

{"title":"Tumor immune cell targeting chimeras reprogram tumor-associated macrophages","authors":"Mariko Morimoto, David S. Roberts, Ru M. Wen, Ell Handy, Eric E. Peterson, Grace M. Stepek, Nicholas A. Till, James D. Brooks, Carolyn R. Bertozzi","doi":"10.1038/s41589-026-02258-2","DOIUrl":"10.1038/s41589-026-02258-2","url":null,"abstract":"Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis but also a dominant cell population, with tumor-associated macrophages (TAMs) comprising up to 50% solid tumor mass. Immunotherapies such as immune checkpoint inhibitors derive efficacy from this cancer–immune interface; however, immune-related adverse events from systemic blockade remain a major challenge. To address this need for potent, tumor-specific immunotherapies, we developed tumor immune cell targeting chimeras (TICTACs) that selectively deplete immune checkpoint receptors such as SIRPα from TAM surfaces. These chimeras consist of a synthetic ligand targeting CD206, a TAM marker, conjugated to a nonblocking antibody that binds to the checkpoint receptor without inhibiting it. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs drive robust checkpoint degradation in CD206high macrophages, with no effect on CD206low cells. This decoupling of antibody selectivity from blocking function presents a new paradigm for tumor-specific immunotherapies. Tumor-associated macrophages (TAMs) predominantly adopt an M2-like pro-tumor phenotype, promoting anti-inflammatory signaling and cancer cell metastasis. Now, tumor immune cell targeting chimeras enable targeted degradation of immune checkpoint receptor SIRPα on TAMs to reprogram TAMs.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 11","pages":"1822-1833"},"PeriodicalIF":15.8,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409202","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

Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes. 海洋细菌黄酶中大麻素环化酶活性的结构和生化基础。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-07 DOI: 10.1038/s41589-026-02257-3

Anna C Love, Harshverdhan Sirohi, Felix M Hubert, Ying-Chieh Kao, Daniel E Quinnell, Tian Lan, Ryan Gappy, Marissa Sheehy, Jonathan Hsu, Adrian Lee, Liana Zangwill, Timothy Chang, Bruce A Palfey, Geoffrey Chang, Bradley S Moore

{"title":"Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes.","authors":"Anna C Love, Harshverdhan Sirohi, Felix M Hubert, Ying-Chieh Kao, Daniel E Quinnell, Tian Lan, Ryan Gappy, Marissa Sheehy, Jonathan Hsu, Adrian Lee, Liana Zangwill, Timothy Chang, Bruce A Palfey, Geoffrey Chang, Bradley S Moore","doi":"10.1038/s41589-026-02257-3","DOIUrl":"10.1038/s41589-026-02257-3","url":null,"abstract":"The marine bacterial flavoenzymes Clz9 and Tcz9 can process cannabigerolic acid to the minor cannabinoid, cannabichromenic acid (CBCA); however, the mechanistic details of this extrinsic transformation are still obscure. Here we report a thorough analysis of CBCA formation by Clz9 and Tcz9 through high-resolution crystallographic characterization, biochemical analysis and spectroscopic interrogation. Our work reveals that Clz9 and Tcz9 use different biochemical mechanisms from Cannabis cyclases and each other in their production of CBCA. Collection of a high-resolution substrate-bound structure provides additional key insights into how active site architecture affects substrate binding and stereoselectivity. Engineering approaches improve the stereoselectivity of CBCA formation by Clz9 and Tcz9, providing access to (R) and (S)-CBCA. Collectively, our work advances understanding of enzymatic cannabinoid formation and cements Clz9 and Tcz9 as two unique members of the BBE-like enzyme family with encouraging potential for biocatalytic cannabinoid production applications.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405090","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

Cephalotaxinone enzymes reveal a whole plant model for homoharringtonine biosynthesis. 头孢他辛酮酶揭示了一种全植物高杉酸酯碱生物合成模式。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-06 DOI: 10.1038/s41589-026-02260-8

Yaereen Dho, Kevin Smith, Elizabeth S Sattely

{"title":"Cephalotaxinone enzymes reveal a whole plant model for homoharringtonine biosynthesis.","authors":"Yaereen Dho, Kevin Smith, Elizabeth S Sattely","doi":"10.1038/s41589-026-02260-8","DOIUrl":"10.1038/s41589-026-02260-8","url":null,"abstract":"Homoharringtonine (HHT) is a plant-derived protein translation inhibitor used widely in ribosomal profiling and as a treatment for chronic myeloid leukemia approved by the US Food and Drug Administration. HHT is commercially semisynthesized from the alkaloid core cephalotaxine (CET) extracted from endangered Cephalotaxus species. Despite its importance, the CET/HHT biosynthetic pathway remains unresolved. Here, we use paired untargeted metabolomics (stable-isotope precursor feeding) and transcriptomics to elucidate a near-complete CET biosynthesis. We show that, while CET is biosynthesized only in growing root tips, CET and HHT accumulate throughout the plant. We identify seven pathway intermediates and six enzymes-including cytochrome P450s, an atypical short-chain dehydrogenase and a 2-oxoglutarate-dependent dioxygenase-that enable carbon excision and CET/HHT pentacyclic backbone formation to produce cephalotaxinone, the likely direct precursor of CET. This study establishes a metabolic route to the HHT core and suggests a whole-plant coordination model, in which cephalotaxinone is produced in root tips and distributed for elaboration into HHT.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":" ","pages":""},"PeriodicalIF":15.8,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397343","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

AI decodes protein–ligand binding AI解码蛋白质-配体结合。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-06 DOI: 10.1038/s41589-026-02268-0

Chao Shen, Tingjun Hou

引用次数: 0

Artificial metalloenzymes in complex biological environments 复杂生物环境中的人工金属酶。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-07-03 DOI: 10.1038/s41589-026-02249-3

Guto G. Rhys

{"title":"Artificial metalloenzymes in complex biological environments","authors":"Guto G. Rhys","doi":"10.1038/s41589-026-02249-3","DOIUrl":"10.1038/s41589-026-02249-3","url":null,"abstract":"Artificial metalloenzymes (ArMs) are proteins engineered to contain metal cofactors that often catalyze chemical reactions rarely or never observed in natural biological processes. They hold promise for applications including fine-chemical production, control of cellular function and therapeutics. Many of these applications are difficult to achieve due to cofactor inactivation in complex biological environments and cofactor-induced cellular stress. In this study, I explore the most recent strategies for developing robust, biocompatible ArMs that function in cell lysates, on cell surfaces or intracellularly. The pros and cons of developing and using ArMs in these three environments are described. I also examine how active ArMs might tolerate their environment, and the outstanding challenges and opportunities, including the need for simple methods of construction, improved catalytic performance and exploration of other reactions and microorganisms. Bringing transition-metal catalysis into biological systems remains challenging. Here the author examines how artificial metalloenzymes can be made to function across biological settings, from cell extracts to cell surfaces and intracellular environments.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"22 10","pages":"1-13"},"PeriodicalIF":15.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379694","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

Cryo-EM sheds light on the mechanism of human telomerase inhibition by BIBR1532. Cryo-EM揭示了BIBR1532抑制人端粒酶的机制。

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2026-07-03 DOI: 10.1038/s41589-026-02277-z

引用次数: 0

Allosteric disordering of eIF2B regulates the integrated stress response. eIF2B的变构紊乱调节综合应激反应。

IF 14.8 1区生物学

Nature chemical biology Pub Date : 2026-06-29 DOI: 10.1038/s41589-026-02256-4

Udit Dalwadi,Advait Subramanian,Aniliese Deal,Julia E Conrad,Tamara Nadjsombati,Meera Venkatesh,Morgane Boone,Pascal F Egea,Lingjie He,Nimit Jain,D John Lee,Yuwei Liu,Lucas C Reineke,Kazuki Saito,Nathaniel Talledge,Hannah Toutkoushian,Maxence Le Vasseur,Francesca Zappa,Raoul J de Groot,Diego Acosta-Alvear,Christopher P Arthur,Jodi Nunnari,Susan Marqusee,Rosalie E Lawrence,Mauro Costa-Mattioli,James J Crawford,Frank J M van Kuppeveld,Tristan I Croll,Peter Walter,Adam Frost

{"title":"Allosteric disordering of eIF2B regulates the integrated stress response.","authors":"Udit Dalwadi,Advait Subramanian,Aniliese Deal,Julia E Conrad,Tamara Nadjsombati,Meera Venkatesh,Morgane Boone,Pascal F Egea,Lingjie He,Nimit Jain,D John Lee,Yuwei Liu,Lucas C Reineke,Kazuki Saito,Nathaniel Talledge,Hannah Toutkoushian,Maxence Le Vasseur,Francesca Zappa,Raoul J de Groot,Diego Acosta-Alvear,Christopher P Arthur,Jodi Nunnari,Susan Marqusee,Rosalie E Lawrence,Mauro Costa-Mattioli,James J Crawford,Frank J M van Kuppeveld,Tristan I Croll,Peter Walter,Adam Frost","doi":"10.1038/s41589-026-02256-4","DOIUrl":"https://doi.org/10.1038/s41589-026-02256-4","url":null,"abstract":"The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"36 1","pages":""},"PeriodicalIF":14.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349136","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

A tail of two ligases 由两个连接链组成的尾巴。

IF 15.8 1区生物学

Nature chemical biology Pub Date : 2026-06-25 DOI: 10.1038/s41589-026-02255-5

Yalong Cheng, Ting Han

引用次数: 0