The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding.
The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding.
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DOI：
10.2210/pdb1tnf/pdb
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发表时间：
1990-01
期刊：
影响因子：
--
通讯作者：
M. Eck;S. Sprang
中科院分区：
文献类型：
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作者：
M. Eck;S. Sprang
肿瘤坏死因子（TNF-α），一种由巨噬细胞分泌的蛋白质激素，其三维结构已通过X射线晶体学以2.6 A的分辨率确定。使用从五个重原子衍生物收集的数据通过多个同晶置换确定相。通过真实的空间对称平均，利用TNF-α三聚体的非晶体学3重对称性，进一步改进了多个同晶置换相。与已知的TNF-α氨基酸序列相对应的原子模型很容易构建到用这些改进的相计算的电子密度图中。17，350-道尔顿单体形成具有“卷曲”拓扑结构的细长的反平行β-折叠片夹层。三个单体围绕3重对称轴紧密缔合以形成紧凑的钟形三聚体。该模型的检查和已知的蛋白质结构的比较揭示了惊人的结构同源性的几种病毒外壳蛋白，特别是卫星烟草坏死病毒。在TNF-α和光敏素（TNF-β，已知与TNF-α结合相同受体的相关细胞因子）之间保守的残基的位置表明，光敏素与TNF-α一样，作为三聚体与受体结合，并且与受体相互作用的一般位点位于三聚体的“基部”。
The three-dimensional structure of tumor necrosis factor (TNF-alpha), a protein hormone secreted by macrophages, has been determined at 2.6 A resolution by x-ray crystallography. Phases were determined by multiple isomorphous replacement using data collected from five heavy atom derivatives. The multiple isomorphous replacement phases were further improved by real space symmetry averaging, exploiting the noncrystallographic 3-fold symmetry of the TNF-alpha trimer. An atomic model corresponding to the known amino acid sequence of TNF-alpha was readily built into the electron density map calculated with these improved phases. The 17,350-dalton monomer forms an elongated, antiparallel beta-pleated sheet sandwich with a "jelly-roll" topology. Three monomers associate intimately about a 3-fold axis of symmetry to form a compact bell-shaped trimer. Examination of the model and comparison to known protein structures reveals striking structural homology to several viral coat proteins, particularly satellite tobacco necrosis virus. Locations of residues conserved between TNF-alpha and lymphotoxin (TNF-beta, a related cytokine known to bind to the same receptors as TNF-alpha) suggest that lymphotoxin, like TNF-alpha, binds to the receptor as a trimer and that the general site of interaction with the receptor is at the "base" of the trimer.