单个氨基酸取代改变抗原结合特异性。
Single amino acid substitution altering antigen-binding specificity.
作者信息
Rudikoff S, Giusti A M, Cook W D, Scharff M D
出版信息
Proc Natl Acad Sci U S A. 1982 Mar;79(6):1979-83. doi: 10.1073/pnas.79.6.1979.
Abstract
S107, a phosphocholine-binding myeloma protein, has been cloned in soft agar, and an antigen-binding variant has been isolated and characterized. The variant does not bind phosphocholine attached to carrier or as free hapten in solution but does retain antigenic determinants (idiotypes) of the parent. Chain recombination experiments suggest that the defect in binding is entirely in the heavy chain. Amino acid sequence analysis showed a single substitution--glutamic acid to alanine at position 35--in the first hypervariable or complementarity-determining region. In terms of the three-dimensional model of the phosphocholine-binding site, glutamic acid-35 provides a hydrogen bond to tyrosine-94 of the light chain that appears to be critical for stability of this portion of the binding site. The removal of this bond and the presence of the smaller alanine side chain is thus consistent with the loss in binding activity. These results suggest that small numbers of substitutions in antibodies, such as those presumably introduced by somatic mutation, may in some situations be effective in altering antigen-binding specificity.
摘要
S107是一种结合磷酸胆碱的骨髓瘤蛋白，已在软琼脂中克隆出来，并且一种抗原结合变体已被分离和鉴定。该变体不结合附着于载体的磷酸胆碱或溶液中的游离半抗原，但确实保留了亲本的抗原决定簇（独特型）。链重组实验表明，结合缺陷完全存在于重链中。氨基酸序列分析显示，在第一个高变区或互补决定区的第35位有一个单一替换——谷氨酸被丙氨酸取代。根据磷酸胆碱结合位点的三维模型，35位的谷氨酸为轻链的94位酪氨酸提供氢键，这似乎对结合位点这一部分的稳定性至关重要。因此，这种键的去除以及较小的丙氨酸侧链的存在与结合活性的丧失是一致的。这些结果表明，抗体中的少量替换，比如那些可能由体细胞突变引入的替换，在某些情况下可能有效地改变抗原结合特异性。
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