5dmi

From Proteopedia

Structure of the extracellular domain of the CD40 in complex with CHI220 FAB

PDB ID 5dmi

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Structural highlights

5dmi is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.69Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TNR5_HUMAN Defects in CD40 are the cause of immunodeficiency with hyper-IgM type 3 (HIGM3) [MIM:606843. A rare immunodeficiency syndrome characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE. It results in a profound susceptibility to bacterial infections.^[1]

Function

TNR5_HUMAN Receptor for TNFSF5/CD40LG.

Publication Abstract from PubMed

Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases, and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human-CD40 specific epitope which is divergent in the CD40 of non-human primates. A similarly selected anti-cynomolgus-CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.

Functional antagonism of human CD40 achieved by targeting a unique species-specific epitope.,Yamniuk AP, Suri A, Krystek SR, Tamura J, Ramamurthy V, Kuhn R, Carroll K, Fleener C, Ryseck R, Cheng L, An Y, Drew P, Grant S, Suchard SJ, Nadler SG, Bryson JW, Sheriff S J Mol Biol. 2016 May 21. pii: S0022-2836(16)30169-3. doi:, 10.1016/j.jmb.2016.05.014. PMID:27216500^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12614-9. PMID:11675497 doi:10.1073/pnas.221456898
↑ Yamniuk AP, Suri A, Krystek SR, Tamura J, Ramamurthy V, Kuhn R, Carroll K, Fleener C, Ryseck R, Cheng L, An Y, Drew P, Grant S, Suchard SJ, Nadler SG, Bryson JW, Sheriff S. Functional antagonism of human CD40 achieved by targeting a unique species-specific epitope. J Mol Biol. 2016 May 21. pii: S0022-2836(16)30169-3. doi:, 10.1016/j.jmb.2016.05.014. PMID:27216500 doi:http://dx.doi.org/10.1016/j.jmb.2016.05.014