Szkudlinski M W, Teh N G, Grossmann M, Tropea J E, Weintraub B D
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Nat Biotechnol. 1996 Oct;14(10):1257-63. doi: 10.1038/nbt1096-1257.
We report the generation of superactive analogues of human glycoprotein hormones, with potential applications in thyroid and reproductive disorders. Current biological and structural data were used to rationalize mutagenesis. The 11-20 region in the alpha-subunit with a cluster of lysine residues forms a previously unrecognized domain critical for receptor binding and signal transduction, as well as an important motif in the evolution of glycoprotein hormone activities. The gradual elimination of basic residues in the alpha-subunit coincided with the evolutionary divergence of the hominids from the Old World monkeys. By selective reconstitution of certain critical residues present in homologous nonhuman hormones we have developed human thyroid stimulating hormone and chorionic gonadotropin analogues with substantial increases in receptor binding affinity and bioactivity, thus providing a paradigm for the design of novel therapeutic protein analogues.
我们报告了人类糖蛋白激素超活性类似物的产生，其在甲状腺和生殖系统疾病方面具有潜在应用价值。利用当前的生物学和结构数据来合理指导诱变。α亚基中含有赖氨酸残基簇的11 - 20区域形成了一个此前未被识别的结构域，该结构域对受体结合和信号转导至关重要，同时也是糖蛋白激素活性进化中的一个重要基序。α亚基中碱性残基的逐渐消除与人类从旧世界猴的进化分歧相吻合。通过选择性重建同源非人类激素中存在的某些关键残基，我们开发出了受体结合亲和力和生物活性大幅提高的人促甲状腺激素和绒毛膜促性腺激素类似物，从而为新型治疗性蛋白质类似物的设计提供了范例。
