Livnah O, Stura E A, Johnson D L, Middleton S A, Mulcahy L S, Wrighton N C, Dower W J, Jolliffe L K, Wilson I A
Department of Molecular Biology and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science. 1996 Jul 26;273(5274):464-71. doi: 10.1126/science.273.5274.464.
The functional mimicry of a protein by an unrelated small molecule has been a formidable challenge. Now, however, the biological activity of a 166-residue hematopoietic growth hormone, erythropoietin (EPO), with its class 1 cytokine receptor has been mimicked by a 20-residue cyclic peptide unrelated in sequence to the natural ligand. The crystal structure at 2.8 A resolution of a complex of this agonist peptide with the extracellular domain of EPO receptor reveals that a peptide dimer induces an almost perfect twofold dimerization of the receptor. The dimer assembly differs from that of the human growth hormone (hGH) receptor complex and suggests that more than one mode of dimerization may be able to induce signal transduction and cell proliferation. The EPO receptor binding site, defined by peptide interaction, corresponds to the smaller functional epitope identified for hGH receptor. Similarly, the EPO mimetic peptide ligand can be considered as a minimal hormone, and suggests the design of nonpeptidic small molecule mimetics for EPO and other cytokines may indeed be achievable.
用一种不相关的小分子对蛋白质进行功能模拟一直是一项艰巨的挑战。然而现在，一种由166个残基组成的造血生长激素——促红细胞生成素（EPO）与其1类细胞因子受体的生物学活性，已被一种与天然配体序列无关的20个残基的环肽所模拟。该激动剂肽与EPO受体细胞外结构域复合物的2.8埃分辨率晶体结构表明，一个肽二聚体诱导受体形成几乎完美的双重二聚化。这种二聚体组装不同于人生长激素（hGH）受体复合物，这表明不止一种二聚化模式可能能够诱导信号转导和细胞增殖。由肽相互作用定义的EPO受体结合位点，对应于为hGH受体鉴定出的较小功能表位。同样，EPO模拟肽配体可被视为一种最小化的激素，这表明设计针对EPO和其他细胞因子的非肽类小分子模拟物确实是可行的。
