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

Abstract

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.

Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators

“…Given the structural similarity, Piezo1 also possess the 38-transmembrane-helix topology . The computing power of supercomputers enables molecular dynamics simulations of complex systems containing millions of atoms, thereby promoting the investigation of macromolecular structures. − Chong and colleagues constructed the three-dimensional full-length Piezo1 structural model and confirmed that the trilobular membrane footprint of Piezo1 extends beyond the ion channel. Meanwhile, a combination of amino acid sequence data, available crystal structure, and molecular dynamics simulations facilitates the structural elucidation and biological function of the Piezo1 N-terminal.…”

Traversing through the Dynamic Protein–Protein Interaction Landscape and Conformational Plasticity of PD-1 for Small-Molecule Discovery

“…Nivolumab’s site may serve as a cryptic-allosteric site in PD-1 in the presence of N-loop. Liu et al and previous work from our lab highlighted the dominant role of N-loop in Nivolumab binding that could be a potential target zone on PD-1 to design anti-PD-1 inhibitors. , However, such grooves for small molecules or peptides are not defined in other mAb-bound PD-1 structures.…”

Risk predictive model based on three immune-related gene pairs to assess prognosis and therapeutic sensitivity for hepatocellular carcinoma

“…Programmed cell death 1 (PD-1) has been proven to be a target in HCC in clinical trials. Nivolumab exhibits a high affinity and specific targeting to an epitope of PD-1 [27]. The risk assessment model in our study includes PD-1, which allows the model to more accurately identify patients who are sensitive to immunotherapy and evaluate patients' immune cell infiltration.…”

“…Our prediction model only included 3 immune-related gene pairs with 6 genes to assess both the prognosis and treatment sensitivity to immune and targeted therapy of HCC patients, and it was hard to include all genes reported. Actually, it contained 4 genes which were associated with the prognosis of HCC [20,23,24,27] and 2 genes which have been proved to be related to the prognosis of other tumors [25,26]. Third, we only used public datasets to construct the model and external validation, the practicality should be identified and the detailed relationship should be confirmed by further experiments.…”