8yx1

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CD40 in complex with Bleselumab Fab

Structural highlights

8yx1 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
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

CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.

Crystal structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab.,Asano R, Nakakido M, Perez JF, Ise T, Caaveiro JMM, Nagata S, Tsumoto K Biochem Biophys Res Commun. 2024 Jun 25;714:149969. doi: , 10.1016/j.bbrc.2024.149969. Epub 2024 Apr 18. PMID:38657446^[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
↑ Asano R, Nakakido M, Pérez JF, Ise T, Caaveiro JMM, Nagata S, Tsumoto K. Crystal structures of human CD40 in complex with monoclonal antibodies dacetuzumab and bleselumab. Biochem Biophys Res Commun. 2024 Jun 25;714:149969. PMID:38657446 doi:10.1016/j.bbrc.2024.149969