6x4t

From Proteopedia

(Difference between revisions)

Current revision

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

Structural highlights

6x4t is a 8 chain structure with sequence from Homo sapiens and Orectolobus maculatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.15Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ICOSL_HUMAN The disease may be caused by variants affecting the gene represented in this entry.

Function

ICOSL_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 PubMed

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 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

↑ Yoshinaga SK, Zhang M, Pistillo J, Horan T, Khare SD, Miner K, Sonnenberg M, Boone T, Brankow D, Dai T, Delaney J, Han H, Hui A, Kohno T, Manoukian R, Whoriskey JS, Coccia MA. Characterization of a new human B7-related protein: B7RP-1 is the ligand to the co-stimulatory protein ICOS. Int Immunol. 2000 Oct;12(10):1439-47. PMID:11007762 doi:10.1093/intimm/12.10.1439
↑ Wang S, Zhu G, Chapoval AI, Dong H, Tamada K, Ni J, Chen L. Costimulation of T cells by B7-H2, a B7-like molecule that binds ICOS. Blood. 2000 Oct 15;96(8):2808-13 PMID:11023515
↑ Roussel L, Landekic M, Golizeh M, Gavino C, Zhong MC, Chen J, Faubert D, Blanchet-Cohen A, Dansereau L, Parent MA, Marin S, Luo J, Le C, Ford BR, Langelier M, King IL, Divangahi M, Foulkes WD, Veillette A, Vinh DC. Loss of human ICOSL results in combined immunodeficiency. J Exp Med. 2018 Dec 3;215(12):3151-3164. PMID:30498080 doi:10.1084/jem.20180668
↑ Rujas E, Cui H, Sicard T, Semesi A, Julien JP. Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies. Nat Commun. 2020 Oct 8;11(1):5066. doi: 10.1038/s41467-020-18828-4. PMID:33033255 doi:http://dx.doi.org/10.1038/s41467-020-18828-4

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6x4t"

@@ Line 8: / Line 8: @@
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6x4t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x4t OCA], [https://pdbe.org/6x4t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x4t RCSB], [https://www.ebi.ac.uk/pdbsum/6x4t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x4t ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ICOSL_HUMAN ICOSL_HUMAN] The disease may be caused by variants affecting the gene represented in this entry.
 == Function ==
-[https://www.uniprot.org/uniprot/ICOSL_HUMAN ICOSL_HUMAN] Ligand for the T-cell-specific cell surface receptor ICOS. Acts as a costimulatory signal for T-cell proliferation and cytokine secretion; induces also 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).
+[https://www.uniprot.org/uniprot/ICOSL_HUMAN ICOSL_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).<ref>PMID:11007762</ref> <ref>PMID:11023515</ref> <ref>PMID:30498080</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

6x4t

From Proteopedia

Current revision

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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