8ayh

From Proteopedia

Structure of Complement C5 in Complex with small molecule inhibitor and CVF

Structural highlights

8ayh is a 3 chain structure with sequence from Homo sapiens and Naja kaouthia. This structure supersedes the now removed PDB entry 6i2x. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VCO3_NAJKA Complement-activating protein in cobra venom. It is a structural and functional analog of complement component C3b, the activated form of C3. It binds factor B (CFB), which is subsequently cleaved by factor D (CFD) to form the bimolecular complex CVF/Bb. CVF/Bb is a C3/C5 convertase that cleaves both complement components C3 and C5. Structurally, it resembles the C3b degradation product C3c, which is not able to form a C3/C5 convertase. Unlike C3b/Bb, CVF/Bb is a stable complex and completely resistant to the actions of complement regulatory factors H (CFH) and I (CFI). Therefore, CVF continuously activates complement resulting in the depletion of complement activity.

Publication Abstract from PubMed

The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.

A small-molecule inhibitor of C5 complement protein.,Jendza K, Kato M, Salcius M, Srinivas H, De Erkenez A, Nguyen A, McLaughlin D, Be C, Wiesmann C, Murphy J, Bolduc P, Mogi M, Duca J, Namil A, Capparelli M, Darsigny V, Meredith E, Tichkule R, Ferrara L, Heyder J, Liu F, Horton PA, Romanowski MJ, Schirle M, Mainolfi N, Anderson K, Michaud GA Nat Chem Biol. 2019 Jul;15(7):666-668. doi: 10.1038/s41589-019-0303-9. Epub 2019 , Jun 17. PMID:31209353^[1]

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

References

↑ Jendza K, Kato M, Salcius M, Srinivas H, De Erkenez A, Nguyen A, McLaughlin D, Be C, Wiesmann C, Murphy J, Bolduc P, Mogi M, Duca J, Namil A, Capparelli M, Darsigny V, Meredith E, Tichkule R, Ferrara L, Heyder J, Liu F, Horton PA, Romanowski MJ, Schirle M, Mainolfi N, Anderson K, Michaud GA. A small-molecule inhibitor of C5 complement protein. Nat Chem Biol. 2019 Jul;15(7):666-668. doi: 10.1038/s41589-019-0303-9. Epub 2019 , Jun 17. PMID:31209353 doi:http://dx.doi.org/10.1038/s41589-019-0303-9