Molecular dynamics of the immune checkpoint Programmed Cell Death Protein I, PD-1: Conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

Roither, Bernhard; Oostenbrink, Chris; Schreiner, Wolfgang

doi:10.1109/bibm47256.2019.8983404

Cited by 4 publications

(6 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As opposed to this, the BC-loop seemed to increase motility when bound to the natural ligand, PD-L1. The dynamics of the BC-loop has already been evaluated in our previous work [20] where we were able to show that it exhibits three different conformations depending on the binding partner.…”

Section: Local Flexibilitymentioning

confidence: 89%

“…An approach similar to our previous work was taken [20] using the notation PD-1 Apo , PD-1 PD-L1 , PD-1 Niv, and PD-1 Pem when referring to the respective simulated system (PD-1 unbound, the PD-1/PD-L1 complex, the PD-1/nivolumab complex and the PD-1/pembrolizumab complex).…”

Section: Methodsmentioning

confidence: 99%

“…With increasing length of trajectories, we first observed an increase in N c , but around 150 ns per system, N c levelled off, indicating that more simulation time did not lead to the sampling of additional areas of phase space and that the simulation time of 200 ns per system could be considered sufficient for convergence. Figure S1 shows how the number of clusters first increased with total simulation time and started to level off after about 600 ns (see also [20]). A small continuous increase was to be expected, but the clusters later appearing were typically clusters with only 1-2 observations per cluster.…”

Section: Key Conformations Identified By Clusteringmentioning

confidence: 99%

See 2 more Smart Citations

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

Roither

Oostenbrink

Koelbl

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

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’ conformation of CC′-loop in apo-PD-1, already known from literature. Unsupervised clustering also surprisingly reproduced the natural ligand, PD-L1, exclusively stabilizing the ‘closed’ conformation, as also known from literature. Nivolumab, like PD-L1, was found to shift the equilibrium towards the ‘closed’ conformation, in accordance with the conformational selection model. Pembrolizumab, on the other hand, induced a third conformation of the CC′-loop which has not been described to date: Relative to the conformation ‘open’ the, CC′-loop turned 180° to form a new conformation which we called ‘overturned’. We show that the combination of clustering and multidimensional scaling is a fast, easy, and powerful method in analyzing structural changes in proteins. Possible refined antibodies or new small molecular compounds could utilize the flexibility of the CC′-loop to improve immunotherapy.

show abstract

Section: Local Flexibilitymentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Key Conformations Identified By Clusteringmentioning

confidence: 99%

See 1 more Smart Citation

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

Roither

Oostenbrink

Koelbl

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Also the conformational dynamics of PD-L1 were studied with MD [ 14 , 15 ]. We have also performed preliminary investigations [ 16 ] which are supplemented in the current work.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Various cancer types overexpress PD-L1 to evade the immune system by inducing apoptosis in tumor-specific CD8+ T cells. Roither et al [ 7 ] present the results of the first molecular dynamics simulations of PD-1 with a complete extracellular domain, focusing on the role of the BC-loop of PD-1 upon binding PD-L1 or nivolumab. Due to the structural differences of the BC-loop, a signal transduction based on active conformation cannot be ruled out.…”

Section: Topics Coveredmentioning

confidence: 99%

Toward computational modelling on immune system function

2020

View full text Add to dashboard Cite

The 3rd edition of the computational methods for the immune system function workshop has been held in San Diego, CA, in conjunction with the IEEE International Conference on Bioinformatics and Biomedicine (BIBM 2019) from November 18 to 21, 2019. The workshop has continued its growing tendency, with a total of 18 accepted papers that have been presented in a full day workshop. Among these, the best 10 papers have been selected and extended for presentation in this special issue. The covered topics range from computer-aided identification of T cell epitopes to the prediction of heart rate variability to prevent brain injuries, from In Silico modeling of Tuberculosis and generation of digital patients to machine learning applied to predict type-2 diabetes risk.

show abstract

Molecular dynamics of the immune checkpoint Programmed Cell Death Protein I, PD-1: Conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

Cited by 4 publications

References 16 publications

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

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

Molecular dynamics of the immune checkpoint programmed cell death protein I, PD-1: conformational changes of the BC-loop upon binding of the ligand PD-L1 and the monoclonal antibody nivolumab

Toward computational modelling on immune system function

Contact Info

Product

Resources

About