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首页> 外文期刊>Biochemistry >SOLUTION CONFORMATION OF THE EXTRACELLULAR DOMAIN OF THE HUMAN TUMOR NECROSIS FACTOR RECEPTOR PROBED BY RAMAN AND UV-RESONANCE RAMAN SPECTROSCOPY - STRUCTURAL EFFECTS OF AN ENGINEERED PEG LINKER
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SOLUTION CONFORMATION OF THE EXTRACELLULAR DOMAIN OF THE HUMAN TUMOR NECROSIS FACTOR RECEPTOR PROBED BY RAMAN AND UV-RESONANCE RAMAN SPECTROSCOPY - STRUCTURAL EFFECTS OF AN ENGINEERED PEG LINKER

机译：拉曼光谱和紫外共振拉曼光谱研究的人类肿瘤坏死因子受体胞外域的溶液构象-工程化PEG接头的结构效应

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摘要

The solution structure of the Escherichia coli-expressed extracellular domain, residues 12-172 of the human 55 kDa type I tumor necrosis factor receptor (TNFR) has been probed by Raman (514.5 nm) and ultraviolet-resonance Raman (244 nm) excitations. The Raman spectra have been collected from both the free TNFR domain and an engineered ''dumbbell-like'' derivative, consisting of two mutant receptor moieties linked by a 20 kDa polyethylene glycol (PEG) tether. The results demonstrate a TNFR secondary structure which is rich in beta-sheet and deficient in alpha-helix, consistent with the reported X-ray crystal structure of baculovirus expressed receptor complexed with factor beta [Banner, D. W., D'Arcy, A., Janes, W., Gentz, R., Schoenfeld, H.-J., Broger, C., Loetscher, H., & Lesslauer, W. (1993) Cell 73, 431-445]. Conversely, the solution structure of TNFR differs from the crystal structure in its distribution of disulfide rotamers and in the orientation of its unique indole side chain (tryptophan-107). These differences are attributed, respectively, to N-terminal truncation and factor binding in the TNFR crystal structure. The tryptophan configuration, which is easily monitored in both Raman and UVRR spectra, is proposed as a potential signal of receptor/factor recognition and binding. Application of the Raman probes to the engineered TNFR dumbbell, which is of interest as a potential therapeutic, shows that TNFR moieties of the dumbbell exhibit secondary structures and side chain environments which are indistinguishable from those of the native, wild-type moiety. The results suggest that the PEGylated dumbbell may function as an effective TNFR drug delivery system without the consequence of a deleterious antigenic response.
机译：已通过拉曼（514.5 nm）和紫外共振拉曼（244 nm）激发探测了表达大肠杆菌的细胞外结构域，人类55 kDa I型肿瘤坏死因子受体（TNFR）残基12-172的溶液结构。拉曼光谱是从游离TNFR结构域和工程化的“哑铃状”衍生物中收集的，该衍生物由通过20 kDa聚乙二醇（PEG）系链连接的两个突变受体部分组成。结果表明，TNFR二级结构富含β-折叠而α-螺旋缺失，这与杆状病毒表达的受体与因子β复合的报道X射线晶体结构一致[Banner，DW，D'Arcy，A.， Janes，W.，Gentz，R.，Schoenfeld，H.-J.，Broger，C.，Loetscher，H。，和Lesslauer，W。（1993）Cell 73，431-445]。相反，TNFR的溶液结构与晶体结构的不同之处在于其二硫化物旋转异构体的分布以及其独特的吲哚侧链（色氨酸107）的取向。这些差异分别归因于TNFR晶体结构中的N端截短和因子结合。色氨酸的构型很容易在拉曼光谱和UVRR光谱中监测，被认为是受体/因子识别和结合的潜在信号。将拉曼探针应用于经过工程改造的TNFR哑铃，这是一种潜在的治疗方法，它表明哑铃的TNFR部分具有与天然野生型部分无法区分的二级结构和侧链环境。结果表明，聚乙二醇化哑铃可作为有效的TNFR药物递送系统而无有害抗原反应的结果。

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