Nature chemistry最新文献_第3页

The mechanism of amyloid fibril growth from Φ-value analysis 淀粉样蛋白原纤维生长的机制Φ-value分析

IF 21.8 1区化学

Nature chemistry Pub Date : 2025-01-16 DOI: 10.1038/s41557-024-01712-9

Jacob Aunstrup Larsen, Abigail Barclay, Nicola Vettore, Louise K. Klausen, Lena N. Mangels, Alberto Coden, Jeremy D. Schmit, Kresten Lindorff-Larsen, Alexander K. Buell

{"title":"The mechanism of amyloid fibril growth from Φ-value analysis","authors":"Jacob Aunstrup Larsen, Abigail Barclay, Nicola Vettore, Louise K. Klausen, Lena N. Mangels, Alberto Coden, Jeremy D. Schmit, Kresten Lindorff-Larsen, Alexander K. Buell","doi":"10.1038/s41557-024-01712-9","DOIUrl":"https://doi.org/10.1038/s41557-024-01712-9","url":null,"abstract":"Amyloid fibrils are highly stable misfolded protein assemblies that play an important role in several neurodegenerative and systemic diseases. Although structural information of the amyloid state is now abundant, mechanistic details about the misfolding process remain elusive. Inspired by the Φ-value analysis of protein folding, we combined experiments and molecular simulations to resolve amino-acid contacts and determine the structure of the transition-state ensemble—the rate-limiting step—for fibril elongation of PI3K-SH3 amyloid fibrils. The ensemble was validated experimentally by Tanford β analysis and computationally by free energy calculations. Although protein folding proceeds on funnel-shaped landscapes, here we find that the energy landscape for the misfolding reaction consists of a large ‘golf course’ region, defined by a single energy barrier and transition state, accessing a sharply funnelled region. Thus, misfolding occurs by rare, successful monomer–fibril end collisions interspersed by numerous unsuccessful binding attempts. Taken together, these insights provide a quantitative and highly resolved description of a protein misfolding reaction.<figure></figure>","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"30 1","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering a DNA polymerase for modifying large RNA at specific positions 设计DNA聚合酶，在特定位置修饰大RNA

IF 21.8 1区化学

Nature chemistry Pub Date : 2025-01-13 DOI: 10.1038/s41557-024-01707-6

Dian Chen, Zhanghui Han, Xiaoge Liang, Yu Liu

{"title":"Engineering a DNA polymerase for modifying large RNA at specific positions","authors":"Dian Chen, Zhanghui Han, Xiaoge Liang, Yu Liu","doi":"10.1038/s41557-024-01707-6","DOIUrl":"https://doi.org/10.1038/s41557-024-01707-6","url":null,"abstract":"The synthesis of large RNA with precise modifications at specific positions is in high demand for both basic research and therapeutic applications, but efficient methods are limited. Engineered DNA polymerases have recently emerged as attractive tools for RNA labelling, offering distinct advantages over conventional RNA polymerases. Here, through semi-rational designs, we engineered a DNA polymerase variant and used it to precisely incorporate a diverse range of modifications, including base modifications, 2′-ribose modifications and backbone modifications, into desired positions within RNA. We achieved efficiencies exceeding 85% in the majority of modification cases, demonstrating success in introducing 2′-O-methyl, phosphorothioate, N4-acetylcytidine and a fluorophore to specific sites in eGFP and Firefly luciferase messenger RNA. Our mRNA products with N4-acetylcytidine, 2′-O-methyl and/or phosphorothioate have demonstrated the ability to enhance stability and affect protein production. This method presents a promising tool for the comprehensive functionalization of RNA, enabling the introduction of plentiful modifications irrespective of RNA lengths and sequences.<figure></figure>","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"204 1","pages":""},"PeriodicalIF":21.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Coacervate vesicles assembled by liquid–liquid phase separation improve delivery of biopharmaceuticals 通过液-液相分离组装的凝聚囊泡改善了生物药物的输送

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-13 DOI: 10.1038/s41557-024-01705-8

Ping Wen, Hanwei Huang, Ruizhe Zhang, Hanqi Zheng, Tingxizi Liang, Chuyue Zhuang, Qing Wu, Junxia Wang, Feng Liu, Ke Zhang, Wei Wu, Kaixin He, Funan Liu, Hongjun Li, Zhen Gu

{"title":"Coacervate vesicles assembled by liquid–liquid phase separation improve delivery of biopharmaceuticals","authors":"Ping Wen, Hanwei Huang, Ruizhe Zhang, Hanqi Zheng, Tingxizi Liang, Chuyue Zhuang, Qing Wu, Junxia Wang, Feng Liu, Ke Zhang, Wei Wu, Kaixin He, Funan Liu, Hongjun Li, Zhen Gu","doi":"10.1038/s41557-024-01705-8","DOIUrl":"10.1038/s41557-024-01705-8","url":null,"abstract":"Vesicles play critical roles in cellular materials storage and signal transportation, even in the formation of organelles and cells. Natural vesicles are composed of a lipid layer that forms a membrane for the enclosure of substances inside. Here we report a coacervate vesicle formed by the liquid–liquid phase separation of cholesterol-modified DNA and histones. Unlike a phospholipid-based membrane-bounded vesicle, a coacervate vesicle lacks a membrane structure on the surface and is organized with a high-density liquid layer and a water-filled cavity. Through a straightforward coacervation process, we demonstrate that various biological agents, including virus particles, mRNA, cytokines and peptides, can be innocuously and directly enriched in the liquid phase. In contrast to the droplet-like coacervates that are prone to aggregation challenges, coacervate vesicles display superior kinetic stability, positioning them as a versatile delivery vehicle for biopharmaceuticals. We validate that incorporating oncolytic viruses into these coacervate vesicles endows them with potent oncolytic efficacy and elicits robust anti-tumour immune responses in mouse models. Natural vesicles typically consist of a lipid membrane enclosing substances. Now a coacervate vesicle formed by liquid–liquid phase separation of cholesterol-modified DNA and histones has been developed. Unlike traditional vesicles, these lack a membrane and feature a high-density liquid layer around a water-filled cavity, offering enhanced kinetic stability and potential as a biopharmaceutical delivery system.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 2","pages":"279-288"},"PeriodicalIF":19.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defining proteoform-specific interactions for drug targeting in a native cell signalling environment 在天然细胞信号环境中定义药物靶向的蛋白形式特异性相互作用

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-13 DOI: 10.1038/s41557-024-01711-w

Corinne A. Lutomski, Jack L. Bennett, Tarick J. El-Baba, Di Wu, Joshua D. Hinkle, Sean A. Burnap, Idlir Liko, Christopher Mullen, John E. P. Syka, Weston B. Struwe, Carol V. Robinson

{"title":"Defining proteoform-specific interactions for drug targeting in a native cell signalling environment","authors":"Corinne A. Lutomski, Jack L. Bennett, Tarick J. El-Baba, Di Wu, Joshua D. Hinkle, Sean A. Burnap, Idlir Liko, Christopher Mullen, John E. P. Syka, Weston B. Struwe, Carol V. Robinson","doi":"10.1038/s41557-024-01711-w","DOIUrl":"10.1038/s41557-024-01711-w","url":null,"abstract":"Understanding the dynamics of membrane protein–ligand interactions within a native lipid bilayer is a major goal for drug discovery. Typically, cell-based assays are used, however, they are often blind to the effects of protein modifications. In this study, using the archetypal G protein-coupled receptor rhodopsin, we found that the receptor and its effectors can be released directly from retina rod disc membranes using infrared irradiation in a mass spectrometer. Subsequent isolation and dissociation by infrared multiphoton dissociation enabled the sequencing of individual retina proteoforms. Specifically, we categorized distinct proteoforms of rhodopsin, localized labile palmitoylations, discovered a Gβγ proteoform that abolishes membrane association and defined lipid modifications on G proteins that influence their assembly. Given reports of undesirable side-effects involving vision, we characterized the off-target drug binding of two phosphodiesterase 5 inhibitors, vardenafil and sildenafil, to the retina rod phosphodiesterase 6 (PDE6). The results demonstrate differential off-target reactivity with PDE6 and an interaction preference for lipidated proteoforms of G proteins. In summary, this study highlights the opportunities for probing proteoform–ligand interactions within natural membrane environments. G protein-coupled receptors and their effectors can now be released directly from a lipid bilayer using infrared irradiation for proteoform-level characterization by native top-down mass spectrometry. This represents a critical development for drug discovery, as the direct role of post-translational modifications in protein–protein and protein–drug interactions can be characterized.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 2","pages":"204-214"},"PeriodicalIF":19.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01711-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mimicking of differentiation in pluripotent synthetic cells 多能合成细胞的模拟分化

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-10 DOI: 10.1038/s41557-024-01684-w

引用次数: 0

Synthesis of three-dimensional covalent organic frameworks through a symmetry reduction strategy. 通过对称还原策略合成三维共价有机框架。

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-08 DOI: 10.1038/s41557-024-01715-6

Jianhong Chang, Zeyue Zhang, Haorui Zheng, Hui Li, Jinquan Suo, Chunqing Ji, Fenqian Chen, Shipeng Zhang, Zitao Wang, Valentin Valtchev, Shilun Qiu, Junliang Sun, Qianrong Fang

{"title":"Synthesis of three-dimensional covalent organic frameworks through a symmetry reduction strategy.","authors":"Jianhong Chang, Zeyue Zhang, Haorui Zheng, Hui Li, Jinquan Suo, Chunqing Ji, Fenqian Chen, Shipeng Zhang, Zitao Wang, Valentin Valtchev, Shilun Qiu, Junliang Sun, Qianrong Fang","doi":"10.1038/s41557-024-01715-6","DOIUrl":"https://doi.org/10.1038/s41557-024-01715-6","url":null,"abstract":"Three-dimensional (3D) covalent organic frameworks (COFs) hold significant promise for a variety of applications. However, conventional design approaches using regular building blocks limit the structural diversity of 3D COFs. Here we design and synthesize two 3D COFs, designated as JUC-644 and JUC-645, through a methodology that relies on using eight-connected building blocks with reduced symmetry. Their structures are solved using continuous rotation electron diffraction and high-resolution transmission electron microscopy, which reveal a unique linkage with a double chain structure, a rare phenomenon in COFs. We deconstruct these structures into [4 + 3(+ 2)]-c nets, which leads to six different topologies. Furthermore, JUC-644 demonstrates high adsorption capacity for C3H8 and n-C4H10 (11.28 and 10.45 mmol g-1 at 298 K and 1 bar, respectively), surpassing most known porous materials, with notable selectivity for C3H8/C2H6 and n-C4H10/C2H6. This approach opens avenues for designing intricate architectures and shows the potential of COFs in C2H6 recovery from natural gas liquids.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":" ","pages":""},"PeriodicalIF":19.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Self-assembly of chiroptical ionic co-crystals from silver nanoclusters and organic macrocycles 银纳米团簇和有机大环的共取向离子晶体自组装。

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-08 DOI: 10.1038/s41557-024-01696-6

Yingwei Li, Grant J. Stec, Hong Ki Kim, Surendra Thapa, Shao-Liang Zheng, Arthur McClelland, Jarad A. Mason

{"title":"Self-assembly of chiroptical ionic co-crystals from silver nanoclusters and organic macrocycles","authors":"Yingwei Li, Grant J. Stec, Hong Ki Kim, Surendra Thapa, Shao-Liang Zheng, Arthur McClelland, Jarad A. Mason","doi":"10.1038/s41557-024-01696-6","DOIUrl":"10.1038/s41557-024-01696-6","url":null,"abstract":"Atomically precise nanoclusters can be assembled into ordered superlattices with unique electronic, magnetic, optical and catalytic properties. The co-crystallization of nanoclusters with functional organic molecules provides opportunities to access an even wider range of structures and properties, but can be challenging to control synthetically. Here we introduce a supramolecular approach to direct the assembly of atomically precise silver nanoclusters into a series of nanocluster‒organic ionic co-crystals with tunable structures and properties. By leveraging non-covalent interactions between anionic silver nanoclusters and cationic organic macrocycles of varying sizes, the orientation of nanocluster surface ligands can be manipulated to achieve in situ resolution of enantiopure nanocluster‒organic ionic co-crystals that feature large chiroptical effects. Beyond chirality, this co-crystal assembly approach provides a promising platform for designing functional solid-state nanomaterials through a combination of supramolecular chemistry and atomically precise nanochemistry. The co-crystallization of nanoclusters with functional organic molecules can provide access to superlattices with unique properties, but this process remains synthetically challenging. Now it has been shown that silver nanoclusters and organic macrocycles can be assembled through a supramolecular approach into ionic co-crystals with tunable structures and large chiroptical effects.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 2","pages":"169-176"},"PeriodicalIF":19.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A pseudo-cubic metal–organic cage with conformationally switchable faces for dynamically adaptive guest encapsulation 具有构象可切换面的伪立方金属有机笼，用于动态自适应客体封装。

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-08 DOI: 10.1038/s41557-024-01708-5

Houyang Xu, Tanya K. Ronson, Andrew W. Heard, Paula C. P. Teeuwen, Laura Schneider, Philipp Pracht, John D. Thoburn, David J. Wales, Jonathan R. Nitschke

{"title":"A pseudo-cubic metal–organic cage with conformationally switchable faces for dynamically adaptive guest encapsulation","authors":"Houyang Xu, Tanya K. Ronson, Andrew W. Heard, Paula C. P. Teeuwen, Laura Schneider, Philipp Pracht, John D. Thoburn, David J. Wales, Jonathan R. Nitschke","doi":"10.1038/s41557-024-01708-5","DOIUrl":"10.1038/s41557-024-01708-5","url":null,"abstract":"The creation of hosts capable of accommodating different guest molecules may enable these hosts to play useful roles in chemical purifications, among other applications. Metal–organic cages are excellent hosts for various guests, but they generally incorporate rigid structural units that hinder dynamic adaptation to specific guests. Here we report a conformationally adaptable pseudo-cubic cage that can dynamically increase its cavity volume to fit guests with differing sizes. This pseudo-cube incorporates a tetramine subcomponent with 2,6-naphthalene arms that cooperatively adopt a non-planar conformation, enabling the cage faces to switch between endo and exo states. A wide range of guest molecules were observed to bind within the cavity of this cage, spanning a range of sizes from 46% to 154% of the cavity volume of the empty cage. Experimental and computational evidence characterizes the flipping of cage faces from endo to exo, expanding the cavity upon binding of larger guests. Synthetic nanocages that can adapt the size and shape of their cavity in response to a given guest have potential applications in various areas, including chemical purification. Now a flexible, pseudo-cubic metal–organic cage has been developed that is able to dynamically expand its cavity from 46% to 154% of its initial volume by flipping its cage faces.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 2","pages":"289-296"},"PeriodicalIF":19.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01708-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Remote control of chirality in hybrid perovskite materials 杂化钙钛矿材料手性的远程控制

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-07 DOI: 10.1038/s41557-024-01694-8

Ghewa AlSabeh, Mengqiong Zhu, Jovana V. Milić

引用次数: 0

Practical electronics and robotics for chemists 化学家的实用电子学和机器人技术

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-07 DOI: 10.1038/s41557-024-01703-w

Pawel L. Urban

引用次数: 0