Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation

Frontiers in Molecular Biosciences

Guangjian Liu¹  Wenping Liu²  Gangping Zhang²  Shengsheng Lai²  Ting Chen²  Haoyu Jin² 

[1] Clinical Data Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China;Guangdong Food and Drug Vocational College, Guangzhou, China;

关键词: PD-1;    nivolumab;    N-terminal loop;    molecular dynamics simulation;    two-step model;   

DOI  :  10.3389/fmolb.2020.574759

来源: DOAJ

【 摘 要 】

The blockade of immune checkpoints, such as programmed death receptor 1 (PD-1) and programmed death ligand 1 protein (PD-L1), is a promising therapeutic approach in cancer immunotherapy. Nivolumab, a humanized IgG4 antibody targeting PD-1, was approved by the US Food and Drug Administration for several cancers in 2014. Crystal structures of the nivolumab/PD-1 complex show that the epitope of PD-1 locates at the IgV domain (including the FG and BC loops) and the N-terminal loop. Although the N-terminal loop of PD-1 has been shown to play a dominant role in the complex interface of the static structure, its role in the dynamic binding process has not been illustrated clearly. Here, eight molecular systems were established for nivolumab/PD-1 complex, and long-time molecular dynamics simulations were performed for each. Results showed that the N-terminal loop of PD-1 prefers to bind with nivolumab to stabilize the interface between IgV and nivolumab. Furthermore, the binding of the N-terminal loop with nivolumab induces the rebinding between the IgV domain and nivolumab. Thus, we proposed a two-step binding model for the nivolumab/PD-1 binding, where the interface switches to a high-affinity state with the help of the N-terminal loop. This finding suggests that the N-terminal loop of PD-1 might be a potential target for anti-PD-1 antibody design, which could serve as an important gatekeeper for the anti-PD-1 antibody binding.

【 授权许可】

Unknown