6X4G

Crystal structure of ICOS in complex with ICOS-L and an anti ICOS-L VNAR domain

Summary for 6X4G

• Entry DOI: 10.2210/pdb6x4g/pdb
• Descriptor: Inducible T-cell costimulator, ICOS ligand, anti ICOS-L VHH domain VNAR, ... (6 entities in total)
• Functional Keywords: immune checkpoint, receptors, glycoproteins, immune system, t-cell, b-cell
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 57412.44

Authors

Rujas, E.,Sicard, T.,Julien, J.P. (deposition date: 2020-05-22, release date: 2020-10-14, Last modification date: 2023-10-18)

Primary citation

Rujas, E.,Cui, H.,Sicard, T.,Semesi, A.,Julien, J.P.
Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies.
Nat Commun, 11:5066-5066, 2020

PubMed Abstract: The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Å resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors.

PubMed: 33033255
DOI: 10.1038/s41467-020-18828-4

Experimental method

X-RAY DIFFRACTION (3.5 Å)