Nature chemistry最新文献_第10页

Author Correction: Discovery of the selenium-containing antioxidant ovoselenol derived from convergent evolution 作者更正：发现源自趋同演化的含硒抗氧化剂卵硒醇。

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-21 DOI: 10.1038/s41557-025-01739-6

Chase M. Kayrouz, Kendra A. Ireland, Vanessa Y. Ying, Katherine M. Davis, Mohammad R. Seyedsayamdost

引用次数: 0

Isolation of a planar π-aromatic Bi5− ring in a cobalt-based inverse-sandwich-type complex 钴基反三明治型配合物中平面π-芳香Bi5−环的分离

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-20 DOI: 10.1038/s41557-024-01713-8

Julia Rienmüller, Benjamin Peerless, Sagar Paul, Florian Bruder, Wolfgang Wernsdorfer, Florian Weigend, Stefanie Dehnen

{"title":"Isolation of a planar π-aromatic Bi5− ring in a cobalt-based inverse-sandwich-type complex","authors":"Julia Rienmüller, Benjamin Peerless, Sagar Paul, Florian Bruder, Wolfgang Wernsdorfer, Florian Weigend, Stefanie Dehnen","doi":"10.1038/s41557-024-01713-8","DOIUrl":"10.1038/s41557-024-01713-8","url":null,"abstract":"Monocyclic π-aromatic compounds are ubiquitous throughout almost all fields of natural sciences—as synthons in industrial processes, as ligands of metal complexes for catalysis or sensing and as bioactive molecules. Planar organocycles stand out through their specific way of overcoming electron deficiency by a non-localizable set of (4n + 2)π electrons. By contrast, all-metal aromatic monocycles are still rare, as metal atoms prefer to form clusters with multiply bonded atoms instead. This limits the knowledge and potential of corresponding compounds in chemical syntheses or for innovative materials. Here we report the successful generation of Bi5−, the heaviest analogue of (C5H5)−. Its use as a ligand in [{IMesCo}2(µ,η5:η5-Bi5)] (1) was realized by reacting (TlBi3)2− with [(IMes)2CoCl] (where IMes is bis(1,3-(2,4,6-trimethylphenyl))imidazol-2-ylidene) in ortho-difluorobenzene. Compound 1 is mixed-valence Co0/CoI as verified by µ-SQUID measurements and density functional theory, and embeds the planar Bi5− cycle in an inverse-sandwich-type manner. Capturing Bi5− represents a landmark in the chemistry of all-metal aromatic molecules and defines a new era for aromatic compounds. All-metal aromatic monocycles are still rare, in contrast to their ubiquitous organic counterparts, because metal atoms tend to form clusters with multiply bonded atoms instead. Now a planar aromatic Bi5− ring has been synthesized as part of a mixed-valence Co0/CoI inverse-sandwich-type complex.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 4","pages":"547-555"},"PeriodicalIF":19.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41557-024-01713-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990440","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

An open-shell Ir(II)/Ir(IV) redox couple outperforms an Ir(I)/Ir(III) pair in olefin isomerization 在烯烃异构化中，开壳Ir(II)/Ir（IV）氧化还原对的性能优于Ir(I)/Ir（III）氧化还原对

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-20 DOI: 10.1038/s41557-024-01722-7

Alejandra Pita-Milleiro, Nereida Hidalgo, Juan J. Moreno, Israel Fernández, Jesús Campos

{"title":"An open-shell Ir(II)/Ir(IV) redox couple outperforms an Ir(I)/Ir(III) pair in olefin isomerization","authors":"Alejandra Pita-Milleiro, Nereida Hidalgo, Juan J. Moreno, Israel Fernández, Jesús Campos","doi":"10.1038/s41557-024-01722-7","DOIUrl":"10.1038/s41557-024-01722-7","url":null,"abstract":"Open-shell systems based on first-row transition metals and their involvement in various catalytic processes are well explored. By comparison, mononuclear open-shell complexes of precious transition metals remain underdeveloped. This is particularly true for IrII complexes, as there is very limited information available regarding their application in catalysis. Here we show that a family of IrII metalloradicals, featuring a C6H3-2,6-(OP(tBu)2)2 (POCOP) pincer ligand, effectively catalyses olefin isomerization—a key step in alkane metathesis—exhibiting up to 20 times higher activity than their IrI counterparts. Computational studies reveal that the IrII/IrIV redox cycling enables faster kinetics than the traditional IrI/IrIII pathway owing to reduced barriers for the oxidative addition and reductive elimination steps. Thus, this study presents a redox catalyst involving an IrII/IrIV pair, highlighting the capabilites of precious-metal systems that extend beyond traditional redox cycles. These findings emphasize the need for expanding catalytic design principles, especially for platinum-group metals. The chemistry of precious-metal-based open-shell mononuclear complexes remains underdeveloped. Now it has been shown that iridium metalloradicals enable Ir(II)/Ir(IV) redox cycles and catalyse olefin isomerization more efficiently than their more commonly used closed-shell analogues, which typically operate through Ir(I)/Ir(III) or Ir(III)/Ir(V) cycles.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 4","pages":"606-613"},"PeriodicalIF":19.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990439","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

Light-promoted aromatic denitrative chlorination 光促进芳香脱硝氯化

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-20 DOI: 10.1038/s41557-024-01728-1

Tiantian Liang, Zhen Lyu, Ye Wang, Wenyan Zhao, Ruocheng Sang, Gui-Juan Cheng, Fei Ye

{"title":"Light-promoted aromatic denitrative chlorination","authors":"Tiantian Liang, Zhen Lyu, Ye Wang, Wenyan Zhao, Ruocheng Sang, Gui-Juan Cheng, Fei Ye","doi":"10.1038/s41557-024-01728-1","DOIUrl":"10.1038/s41557-024-01728-1","url":null,"abstract":"Nitroarenes are readily accessible bulk chemicals and can serve as versatile starting materials for a series of synthetic reactions. However, due to the inertness of the CAr–NO2 bond, the direct denitrative substitution reaction with unactivated nitroarenes remains challenging. Chemists rely on sequential reduction and diazotization followed by the Sandmeyer reaction or the nucleophilic aromatic substitution of activated nitroarenes to realize nitro group transformations. Here we develop a general denitrative chlorination reaction under visible-light irradiation, in which the chlorine radical replaces the nitro moiety through the cleavage of the CAr–NO2 bond. This practical method works with a wide range of unactivated nitro(hetero)arenes and nitroalkenes, is not sensitive to air or moisture and can proceed smoothly on a decagram scale. This transformation differs fundamentally from previous nucleophilic aromatic substitution reactions under thermal conditions in both synthesis and mechanism. Density functional theory calculations reveal the possible pathway for the substitution reaction. Due to the inert CAr–NO2 bond, direct denitrative substitution reactions with unactivated nitroarenes are challenging. Now, using visible-light irradiation, a strategy has been developed to enable direct aromatic denitrative chlorination. Chlorine radicals can replace the NO2 moiety in a wide range of unactivated nitroarenes as well as nitroalkenes.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 4","pages":"598-605"},"PeriodicalIF":19.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990436","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

Synthesis of pillar-layered metal–organic frameworks with variable backbones through sequence control 通过序列控制合成具有可变骨架的柱状层状金属有机骨架

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-20 DOI: 10.1038/s41557-024-01717-4

Jingjing Yuan, Ming Yang, Bin Yang, Shuting Chen, Zhiqiang Liu, Qingqing Pang, Mingyu Wan, Anmin Zheng, Binbin Tu

{"title":"Synthesis of pillar-layered metal–organic frameworks with variable backbones through sequence control","authors":"Jingjing Yuan, Ming Yang, Bin Yang, Shuting Chen, Zhiqiang Liu, Qingqing Pang, Mingyu Wan, Anmin Zheng, Binbin Tu","doi":"10.1038/s41557-024-01717-4","DOIUrl":"10.1038/s41557-024-01717-4","url":null,"abstract":"The properties and functions of metal–organic frameworks (MOFs) can be tailored by tuning their structure, including their shape, porosity and topology. However, the design and synthesis of complex structures in a predictable manner remains challenging. Here we report the preparation of a series of isomeric pillar-layered MOFs, and we show that their three-dimensional topology can be controlled by altering the layer stacking. This enables variability on the backbone structure, as well as diverse spatial arrangements of pillars and the partitioning of pore space into several kinds of cages packing in distinct sequences. These sequence-controlled MOFs (SC-MOF-1–6) showcase ultrahigh benzene capture capacities at low-pressure and high volumetric and gravimetric uptake performances in high-pressure methane storage. We provide the construction principles of the SC-MOFs and predict nearly 2,000 possible SC-networks with sophisticated composition sequences at the atomic level by using a Python script. The tailoring of reticular materials is key for enhancing the complexity and diversity of their structure and function. Now, a series of isomeric pillar-layered metal–organic frameworks with tunable topologies have been prepared through altering the layer stacking, which enables variability on the backbone structure, pillar spatial arrangements and pore structure.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 3","pages":"421-428"},"PeriodicalIF":19.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990437","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

Vibrational weak and strong coupling modify a chemical reaction via cavity-mediated radiative energy transfer 振动弱耦合和强耦合通过腔体介导的辐射能量传递改变化学反应

IF 19.2 1区化学

Nature chemistry Pub Date : 2025-01-16 DOI: 10.1038/s41557-024-01723-6

Zachary T. Brawley, Sindhana Pannir-Sivajothi, Ju Eun Yim, Yong Rui Poh, Joel Yuen-Zhou, Matthew Sheldon

{"title":"Vibrational weak and strong coupling modify a chemical reaction via cavity-mediated radiative energy transfer","authors":"Zachary T. Brawley, Sindhana Pannir-Sivajothi, Ju Eun Yim, Yong Rui Poh, Joel Yuen-Zhou, Matthew Sheldon","doi":"10.1038/s41557-024-01723-6","DOIUrl":"10.1038/s41557-024-01723-6","url":null,"abstract":"Controlling reaction outcomes through external influences is a central goal in chemistry. Vibrational coupling between molecular vibrations and cavity modes is rapidly emerging as a distinct strategy compared with conventional thermochemical and photochemical methods; however, insight into the fundamental mechanisms remains limited. Here we investigate how vibrational weak and strong coupling in plasmonic nanocavities modifies the thermal dehydration of copper sulfate pentahydrate. We demonstrate that light–matter coupling reduces the onset temperature for dehydration by up to 14 °C, and we attribute this effect to enhanced radiative energy transport that is mediated by resonant electromagnetic modes, eliminating temperature gradients in the coupled system. Our findings provide direct evidence of localized energy transfer leading to modified chemical behaviour in specific regions of high optical density of states. This work establishes a mechanism for modifying thermally driven chemical processes using optical cavities, with implications for the development of catalytic systems that exploit these tailored interactions to achieve targeted reaction control. Vibrational weak and strong light–matter coupling in infrared nanocavities modifies chemical processes. Now it has been shown that this coupling can control thermally driven reactions through enhanced radiative energy transport.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 3","pages":"439-447"},"PeriodicalIF":19.2,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986626","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

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 19.2 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":"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. Amyloid fibrils grow through the recruitment of soluble monomer to the fibril end that propagates the fibril structure. Here the transition state, the rate-limiting conformation, of such a reaction has been characterized by Φ-value analysis. An energy landscape model has been developed and fibril growth rates predicted from first principles.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 3","pages":"403-411"},"PeriodicalIF":19.2,"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

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

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 19.2 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":"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. The demand for large, position-specific modified RNA molecules is high across diverse fields. Now a DNA polymerase has been engineered to enable the efficient and flexible synthesis of such molecules using a pause–restart strategy. This methodology can be implemented in both liquid and hybrid solid–liquid phases.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":"17 3","pages":"382-392"},"PeriodicalIF":19.2,"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

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