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Multiplexed Isotope-Coded Mass Spectrometry Footprinting Enables Broad Heteroatom-Residue Mapping and Uncovers Noncanonical Ligand-Binding Sites in Amyloidosis Proteins

文献类型：期刊论文

作者Yang, Kuoqi1,3; Zheng, Wei3; Bai, Lin1,3; Wang, Kai3; Zhang, Jian3; Wei, Yaqi3; Sun, Guangqiang2,3; Hu, Youhong2,3; Cheng, Ming2,3
刊名ANALYTICAL CHEMISTRY
出版日期2026-01-16
页码13
ISSN号0003-2700
DOI10.1021/acs.analchem.5c04456
通讯作者Hu, Youhong(yhhu@simm.ac.cn) ; Cheng, Ming(chengming@simm.ac.cn)
英文摘要Deciphering novel protein-ligand interaction sites with high structural precision is essential for elucidating protein function and advancing therapeutic development. Mass spectrometry-based protein footprinting offers a powerful means to interrogate binding interfaces; however, broader and more versatile residue labeling is needed to enhance resolution and applicability in complex systems. Here, we developed a footprinting strategy based on Woodward's Reagent K (WRK) targeting heteroatom-containing side chains. The approach is tunable, and it broadly modifies nine nucleophilic residues-Glu, Asp, His, Tyr, Thr, Ser, Lys, Arg, and Cys-representing one of the broadest residue profiles achieved by nonradical footprinting. The WRK scaffold readily accommodates isotope coding, enabling precise, multiplexed quantitative analysis. Applied to two rigid beta-sheet proteins, this method accurately maps native ligand-binding sites across a continuum of binding affinities. Remarkably, WRK footprinting delineates a previously uncharacterized ligand-binding pocket on tetrameric transthyretin (TTR) and reveals a noncanonical fibrillogenesis-inhibitory mechanism mediated by a novel ligand identified through high-throughput affinity mass spectrometry screening. This ligand impedes TTR fibril formation by engaging a distinct pocket separate from the canonical T4 binding site. Altogether, these findings position WRK as an effective tool for resolving noncanonical binding sites with therapeutic potential in structure-based drug discovery.
WOS关键词FAST PHOTOCHEMICAL OXIDATION ; WOODWARDS REAGENT-K ; STRUCTURAL-ANALYSIS ; CARBENE ; DIETHYLPYROCARBONATE ; ACTIVATION ; RESOLUTION ; THYROXINE ; DISTINCT ; REVEALS
资助项目Science and Technology Commission of Shanghai Municipality[24PJA154] ; National Key Research and Development Program of China[2024YFA1306800]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001663763100001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/322688]  
专题中国科学院上海药物研究所
通讯作者Hu, Youhong; Cheng, Ming
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Kuoqi,Zheng, Wei,Bai, Lin,et al. Multiplexed Isotope-Coded Mass Spectrometry Footprinting Enables Broad Heteroatom-Residue Mapping and Uncovers Noncanonical Ligand-Binding Sites in Amyloidosis Proteins[J]. ANALYTICAL CHEMISTRY,2026:13.
APA Yang, Kuoqi.,Zheng, Wei.,Bai, Lin.,Wang, Kai.,Zhang, Jian.,...&Cheng, Ming.(2026).Multiplexed Isotope-Coded Mass Spectrometry Footprinting Enables Broad Heteroatom-Residue Mapping and Uncovers Noncanonical Ligand-Binding Sites in Amyloidosis Proteins.ANALYTICAL CHEMISTRY,13.
MLA Yang, Kuoqi,et al."Multiplexed Isotope-Coded Mass Spectrometry Footprinting Enables Broad Heteroatom-Residue Mapping and Uncovers Noncanonical Ligand-Binding Sites in Amyloidosis Proteins".ANALYTICAL CHEMISTRY (2026):13.

入库方式： OAI收割

来源：上海药物研究所

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