6x4t
Crystal structure of ICOS-L in complex with Prezalumab and VNAR domain
Structural highlights
DiseaseICOSL_HUMAN The disease may be caused by variants affecting the gene represented in this entry. FunctionICOSL_HUMAN Ligand for the T-cell-specific cell surface receptor ICOS. Acts as a costimulatory signal for T-cell proliferation and cytokine secretion (PubMed:11007762, PubMed:11023515, PubMed:30498080). Also induces B-cell proliferation and differentiation into plasma cells. Could play an important role in mediating local tissue responses to inflammatory conditions, as well as in modulating the secondary immune response by co-stimulating memory T-cell function (By similarity). In endothelial cells, required for proper neutrophil transmigration in response to chemoattractants, such as CXCL8/IL8 or N-formyl-methionyl peptides (fMLP) (PubMed:30498080).[1] [2] [3] Publication Abstract from PubMedThe 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 A 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. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies.,Rujas E, Cui H, Sicard T, Semesi A, Julien JP Nat Commun. 2020 Oct 8;11(1):5066. doi: 10.1038/s41467-020-18828-4. PMID:33033255[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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