Pembrolizumab Induces an Unexpected Conformational Change in the CC'-loop of PD-1.

ABSTRACT: To improve cancer immunotherapy, a clearer understanding of key targets such as the immune checkpoint receptor PD-1 is essential. The PD-1 inhibitors nivolumab and pembrolizumab were recently approved by the FDA. The CC'-loop of PD-1 has been identified as a hotspot for drug targeting. Here, we investigate the influence of nivolumab and pembrolizumab on the molecular motion of the CC'-loop of PD-1. We performed molecular dynamics simulations on the complete extracellular domain of PD-1, in complex with PD-L1, and the blocking antibodies nivolumab and pembrolizumab. Conformations of the CC'-loop were analyzed unsupervised with the Daura et al. clustering algorithm and multidimensional scaling. Surprisingly, two conformations found were seen to correspond to the 'open' and 'closed' conformat

SUBMITTER: Roither B 

PROVIDER: S-EPMC7792774 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature