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通过对gp130激活重要残基进行分子模型引导诱变产生白细胞介素-6受体拮抗剂。

Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gp130 activation.

作者信息

Savino R, Lahm A, Salvati A L, Ciapponi L, Sporeno E, Altamura S, Paonessa G, Toniatti C, Ciliberto G

机构信息

Department of Genetics, Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Pomezia, Rome, Italy.

出版信息

EMBO J. 1994 Mar 15;13(6):1357-67. doi: 10.1002/j.1460-2075.1994.tb06389.x.

DOI:10.1002/j.1460-2075.1994.tb06389.x
PMID:7511100
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC394953/
Abstract

Interleukin-6 (IL-6) drives the sequential assembly of a receptor complex formed by the IL-6 receptor (IL-6R alpha) and the signal transducing subunit, gp130. A model of human IL-6 (hIL-6) was constructed by homology using the structure of bovine granulocyte colony stimulating factor. The modeled cytokine was predicted to interact sequentially with the cytokine binding domains of IL-6R alpha and gp130 bridging them in a way similar to that of the interaction between growth hormone and its homodimeric receptor. Several residues on helices A and C which were predicted as contact points between IL-6 and gp130 and therefore essential for IL-6 signal transduction, were subjected to site-directed mutagenesis individually or in combined form. Interestingly, while single amino acid changes never produced major alterations in IL-6 bioactivity, a subset of double mutants of Y31 and G35 showed a considerable reduction of biological activity and were selectively impaired from associating with gp130 in binding assays in vitro, while they maintained wild-type affinity towards hIL-6-R alpha. More importantly, we demonstrated the antagonistic effect of mutant Y31D/G35F versus wild-type IL-6.

摘要

白细胞介素-6（IL-6）驱动由白细胞介素-6受体（IL-6Rα）和信号转导亚基gp130形成的受体复合物的顺序组装。利用牛粒细胞集落刺激因子的结构通过同源性构建了人IL-6（hIL-6）模型。预测该模拟细胞因子会与IL-6Rα和gp130的细胞因子结合域顺序相互作用，以类似于生长激素与其同二聚体受体之间相互作用的方式将它们桥接起来。对螺旋A和C上预测为IL-6与gp130之间接触点且因此对IL-6信号转导至关重要的几个残基进行了单独或组合形式的定点诱变。有趣的是，虽然单个氨基酸变化从未在IL-6生物活性上产生重大改变，但Y31和G35的双突变体亚组显示出生物活性显著降低，并且在体外结合试验中与gp130结合的能力受到选择性损害，而它们对hIL-6-Rα保持野生型亲和力。更重要的是，我们证明了突变体Y31D/G35F对野生型IL-6的拮抗作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/8d8d24e27a78/emboj00054-0125-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/d06a0a4d8663/emboj00054-0120-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/1ad25d943f29/emboj00054-0121-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/531312502ef9/emboj00054-0124-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/02773eba0a35/emboj00054-0125-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/8d8d24e27a78/emboj00054-0125-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/d06a0a4d8663/emboj00054-0120-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/1ad25d943f29/emboj00054-0121-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/531312502ef9/emboj00054-0124-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/02773eba0a35/emboj00054-0125-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7634/394953/8d8d24e27a78/emboj00054-0125-b.jpg

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