Xiaowen Zhou1, Jiangfeng Du1, Wenshan Zhao2, Yanfeng Gao3,4, Xiuman Zhou1, Xiaoshuang Niu1, Wanqiong Li5, Chunxia Chen1, Sifan Lv1, Aijun Wu1, Shanshan Gou1, Yixuan Sun1, Wenjie Zhai1, Lu Qiu1, Yuanming Qi1. 1. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. 2. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. zhaowsh07@zzu.edu.cn. 3. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. gaoyf29@mail.sysu.edu.cn. 4. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, 518107, China. gaoyf29@mail.sysu.edu.cn. 5. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University, Shenzhen, 518107, China.
Abstract
BACKGROUND: TIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Blockade of TIGIT/PVR is considered as a promising strategy in cancer immunotherapy. However, to facilitate the design of inhibitors targeting TIGIT/PVR, the structural characteristics and binding mechanism still need to be further studied. METHODS: In this study, molecular dynamics (MD) simulations and in silico mutagenesis were used to analyze the interaction between TIGIT and its ligand PVR. Then, PVR mutants were designed and their activities were determined by using TIGIT overexpressed Jurkat cells. RESULTS: The results suggested that the loops of PVR (CC' loop, C'C″ loop, and FG loop) underwent a large intra-molecular rearrangement, and more hydrogen bond crosslinking between PVR and TIGIT were formed during MD simulations. The potential residues for PVR to interact with TIGIT were identified and utilized to predict high affinity PVR mutants. Through the biological activity evaluation, four PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) with enhanced affinity to TIGIT were discovered, which could elicit more potent inhibitory effects compared with the wild type PVR. CONCLUSIONS: The MD simulations analysis provided new insights into the TIGIT/PVR interaction model, and the identified PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) could serve as new candidates for immunotherapy to block TIGIT/PVR. Video Abstract.
BACKGROUND: TIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Blockade of TIGIT/PVR is considered as a promising strategy in cancer immunotherapy. However, to facilitate the design of inhibitors targeting TIGIT/PVR, the structural characteristics and binding mechanism still need to be further studied. METHODS: In this study, molecular dynamics (MD) simulations and in silico mutagenesis were used to analyze the interaction between TIGIT and its ligand PVR. Then, PVR mutants were designed and their activities were determined by using TIGIT overexpressed Jurkat cells. RESULTS: The results suggested that the loops of PVR (CC' loop, C'C″ loop, and FG loop) underwent a large intra-molecular rearrangement, and more hydrogen bond crosslinking between PVR and TIGIT were formed during MD simulations. The potential residues for PVR to interact with TIGIT were identified and utilized to predict high affinity PVR mutants. Through the biological activity evaluation, four PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) with enhanced affinity to TIGIT were discovered, which could elicit more potent inhibitory effects compared with the wild type PVR. CONCLUSIONS: The MD simulations analysis provided new insights into the TIGIT/PVR interaction model, and the identified PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) could serve as new candidates for immunotherapy to block TIGIT/PVR. Video Abstract.
Entities:
Keywords:
Cancer immunotherapy; Drug design; Molecular dynamics; Mutagenesis; TIGIT/PVR
Authors: K Satoh-Horikawa; H Nakanishi; K Takahashi; M Miyahara; M Nishimura; K Tachibana; A Mizoguchi; Y Takai Journal: J Biol Chem Date: 2000-04-07 Impact factor: 5.157