8EQ6

PD1 signaling receptor bound to FAB Complex

Summary for 8EQ6

• Entry DOI: 10.2210/pdb8eq6/pdb
• Related: 9HK1
• Descriptor: Programmed cell death protein 1, Antibody FAB light chain, Antibody FAB heavy chain, ... (4 entities in total)
• Functional Keywords: immune signaling receptor fab complex, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 62302.29

Authors

Bjorkelid, C.,Paluch, C.,Robertson, N.J. (deposition date: 2022-10-07, release date: 2023-10-11, Last modification date: 2025-01-22)

Primary citation

Lippert, A.H.,Paluch, C.,Gaglioni, M.,Vuong, M.T.,McColl, J.,Jenkins, E.,Fellermeyer, M.,Clarke, J.,Sharma, S.,Moreira da Silva, S.,Akkaya, B.,Anzilotti, C.,Morgan, S.H.,Jessup, C.F.,Korbel, M.,Gileadi, U.,Leitner, J.,Knox, R.,Chirifu, M.,Huo, J.,Yu, S.,Ashman, N.,Lui, Y.,Wilkinson, I.,Attfield, K.E.,Fugger, L.,Robertson, N.J.,Lynch, C.J.,Murray, L.,Steinberger, P.,Santos, A.M.,Lee, S.F.,Cornall, R.J.,Klenerman, D.,Davis, S.J.
Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases.
Immunity, 57:256-270.e10, 2024

PubMed Abstract: Antibodies can block immune receptor engagement or trigger the receptor machinery to initiate signaling. We hypothesized that antibody agonists trigger signaling by sterically excluding large receptor-type protein tyrosine phosphatases (RPTPs) such as CD45 from sites of receptor engagement. An agonist targeting the costimulatory receptor CD28 produced signals that depended on antibody immobilization and were sensitive to the sizes of the receptor, the RPTPs, and the antibody itself. Although both the agonist and a non-agonistic anti-CD28 antibody locally excluded CD45, the agonistic antibody was more effective. An anti-PD-1 antibody that bound membrane proximally excluded CD45, triggered Src homology 2 domain-containing phosphatase 2 recruitment, and suppressed systemic lupus erythematosus and delayed-type hypersensitivity in experimental models. Paradoxically, nivolumab and pembrolizumab, anti-PD-1-blocking antibodies used clinically, also excluded CD45 and were agonistic in certain settings. Reducing these agonistic effects using antibody engineering improved PD-1 blockade. These findings establish a framework for developing new and improved therapies for autoimmunity and cancer.

PubMed: 38354703
DOI: 10.1016/j.immuni.2024.01.007

Experimental method

X-RAY DIFFRACTION (1.65 Å)