6fax

From Proteopedia

Complex of Human CD40 Ectodomain with Lob 7.4 Fab

Structural highlights

6fax is a 3 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 2.99Å
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

Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.

Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies.,Yu X, Chan HTC, Orr CM, Dadas O, Booth SG, Dahal LN, Penfold CA, O'Brien L, Mockridge CI, French RR, Duriez P, Douglas LR, Pearson AR, Cragg MS, Tews I, Glennie MJ, White AL Cancer Cell. 2018 Mar 3. pii: S1535-6108(18)30062-X. doi:, 10.1016/j.ccell.2018.02.009. PMID:29576376^[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
↑ Yu X, Chan HTC, Orr CM, Dadas O, Booth SG, Dahal LN, Penfold CA, O'Brien L, Mockridge CI, French RR, Duriez P, Douglas LR, Pearson AR, Cragg MS, Tews I, Glennie MJ, White AL. Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies. Cancer Cell. 2018 Mar 3. pii: S1535-6108(18)30062-X. doi:, 10.1016/j.ccell.2018.02.009. PMID:29576376 doi:http://dx.doi.org/10.1016/j.ccell.2018.02.009