Redesigning HVEM Interface for Selective Binding to LIGHT, BTLA, and CD160.
Redesigning HVEM Interface for Selective Binding to LIGHT, BTLA, and CD160.
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DOI：
10.1016/j.str.2020.07.013
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发表时间：
2020-11-03
期刊：
影响因子：
--
通讯作者：
Fiser A
中科院分区：
文献类型：
--
作者：
Shrestha R;Garrett-Thomson SC;Liu W;Almo SC;Fiser A
疱疹病毒进入介体（HVEM）通过共信号传导途径调节T细胞活化的正信号和负信号。HVEM共信号网络的功能障碍与自身免疫、传染病和癌症相关的多种病理学相关，使相关分子成为生物学和治疗上有吸引力的靶标。HVEM使用两种不同的结合界面与来自两个不同超家族的三种配体相互作用。与配体CD 160和免疫球蛋白超家族成员B-和T-淋巴细胞衰减剂（BTLA）的接合与抑制信号相关，而炎症反应通过与来自TNF超家族的LIGHT的相互作用来调节。我们使用残基特异性药效团方法ProtLID通过计算重新设计了HVEM识别界面，以实现可切换的结合特异性。在随后的基于细胞的结合试验中，设计为仅具有单突变或双突变的新界面仅与三种同源配体中的一种或两种表现出选择性结合。Shrestha等人使用基于残基的药效团，一种计算方法来设计HVEM界面的突变，使其对三种同源配体中的一种或两种具有选择性。在细胞测定实验中，25个设计的单点和双点突变体中的15个被证明引入统计学显著的选择性。
Herpes virus entry mediator (HVEM) regulates positive and negative signals for T-cell activation through co-signaling pathways. Dysfunction of the HVEM co-signaling network is associated with multiple pathologies related to autoimmunity, infectious disease and cancer, making the associated molecules biologically and therapeutically attractive targets. HVEM interacts with three ligands from two different superfamilies using two different binding interfaces. The engagement with ligands CD160 and B- and T- lymphocyte attenuator (BTLA), members of immunoglobulin superfamily, is associated with inhibitory signals, whereas inflammatory responses are regulated through the interaction with LIGHT from the TNF superfamily. We computationally redesigned the HVEM recognition interfaces using a residue-specific pharmacophore approach, ProtLID, to achieve switchable binding specificity. In subsequent cell-based binding assays the new interfaces, designed with only single or double mutations, exhibited selective binding to only one or two out of the three cognate ligands. Shrestha et al. uses a residue-based pharmacophore a computational approach to design mutations for the interface of HVEM to make it selective to one or two out of its three cognate ligands. In cell assay experiments 15 of the 25 designed single and double point mutants proved to introduce statistically significant selectivity.
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DOI：
10.4049/jimmunol.0902490
发表时间：
2009-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cheung TC;Oborne LM;Steinberg MW;Macauley MG;Fukuyama S;Sanjo H;D'Souza C;Norris PS;Pfeffer K;Murphy KM;Kronenberg M;Spear PG;Ware CF
通讯作者：
Ware CF
影响因子：
4.4
作者：
Breloer, Minka;Hartmann, Wiebke;Jacobs, Thomas
通讯作者：
Jacobs, Thomas
影响因子：
64.8
作者：
Looger, LL;Dwyer, MA;Hellinga, HW
通讯作者：
Hellinga, HW
影响因子：
46.9
作者：
Lippow, Shaun M.;Wittrup, K. Dane;Tidor, Bruce
通讯作者：
Tidor, Bruce
DOI：
10.1073/pnas.0902115106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Cheung, Timothy C.;Steinberg, Marcos W.;Ware, Carl F.
通讯作者：
Ware, Carl F.