Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop
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RESEARCH
Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BCloop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab Bernhard Roither1, Chris Oostenbrink2 and Wolfgang Schreiner1*
From 3rd International Workshop on Computational Methods for the Immune System Function (CMISF 2019) San Diego, CA, USA. 18-21 November 2019 *Correspondence: wolfgang. [email protected] 1 Institute of Biosimulation and Bioinformatics, Medical University of Vienna, Spitalgasse 23/88.04.510, 1090 Vienna, Austria Full list of author information is available at the end of the article
Abstract Background: The immune checkpoint receptor programmed cell death protein I (PD-1) has been identified as a key target in immunotherapy. PD-1 reduces the risk of autoimmunity by inducing apoptosis in antigen-specific T cells upon interaction with programmed cell death protein ligand I (PD-L1). Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. The clinically used blocking antibody nivolumab binds to PD-1 and inhibits the immunosuppressive interaction with PD-L1. Even though PD-1 is already used as a drug target, the exact mechanism of the receptor is still a matter of debate. For instance, it is hypothesized that the signal transduction is based on an active conformation of PD-1. Results: Here we present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain with a focus on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. We could demonstrate that the BC-loop can form three conformations. Nivolumab binds to the BC-loop according to the conformational selection model whereas PD-L1 induces allosterically a conformational change of the BC-loop. Conclusion: Due to the structural differences of the BC-loop, a signal transduction based on active conformation cannot be ruled out. These findings will have an impact on drug design and will help to refine immunotherapy blocking antibodies. Keywords: PD-1, PD-L1, Nivolumab, Molecular dynamics, BC-loop, Mathematical oncology
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