Computational design of a synthetic PD-1 agonist.
Computational design of a synthetic PD-1 agonist.
复制标题
DOI：
10.1073/pnas.2102164118
复制
发表时间：
2021-07-20
影响因子：
11.1
通讯作者：
Baker D
中科院分区：
文献类型：
--
作者：
Bryan CM;Rocklin GJ;Bick MJ;Ford A;Majri-Morrison S;Kroll AV;Miller CJ;Carter L;Goreshnik I;Kang A;DiMaio F;Tarbell KV;Baker D
程序性细胞死亡蛋白-1(PD-1)抑制抗体，通常被称为检查点抑制物，已经彻底改变了癌症的治疗。然而，PD-1激动剂治疗自身免疫性疾病的需求尚未得到满足。在这里，我们描述了一个小的，稳定的PD-1结合蛋白的从头设计和合成PD-1激动剂的开发。表达在激活的T细胞上的程序性细胞死亡蛋白-1(PD-1)抑制T细胞的功能和增殖，以防止过度的免疫反应，如果这种微妙的平衡向任何一个方向移动，就可能导致疾病。肿瘤细胞通常通过过度表达PD-1配体PD-L1来逃避免疫系统的破坏，从而利用这一途径。或者，如果PD-1途径的功能下降，可能会导致免疫系统的不受控制的激活和自身免疫。通过计算和实验相结合的方法，我们设计了一个超稳的40个残基的微型蛋白PD-MP1，它能在PD-L1界面上与小鼠和人PD-1特异性结合，Kd值为∼100 nM。Apo晶体结构表明，粘结剂按设计折叠，主链RMSD为1.3？，符合设计模型。PD-MP1的三聚化导致了PD-1激动剂，该激动剂强烈地抑制了小鼠T细胞的激活。这种小的、高度稳定的PD-1结合蛋白是通过计算设计的，具有全β界面，这种三聚体激动剂可能有助于自身免疫和炎症性疾病的治疗。
Programmed cell death protein-1 (PD-1) inhibitory antibodies, often referred to as checkpoint inhibitors, have revolutionized the treatment of cancer. However, there is an unmet need for PD-1 agonists to treat autoimmune disorders. Herein, we describe the de novo design of a small, stable PD-1 binding protein and development of a synthetic PD-1 agonist. Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a Kd of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Å to the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.
登录
查看更多内容
影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
3.7
作者：
Bywater RP
通讯作者：
Bywater RP
影响因子：
2.8
作者：
Chen, Cheng;Huang, Qi-Lai;Hua, Zi-Chun
通讯作者：
Hua, Zi-Chun
DOI：
10.1073/pnas.0804453105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Lazar-Molnar, Eszter;Yan, Qingrong;Almo, Steven C.
通讯作者：
Almo, Steven C.