6xzu

From Proteopedia

Complex of C-terminal domain of murine complement C3b with the hC3Nb3 nanobody

Structural highlights

6xzu is a 2 chain structure with sequence from Lama glama 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 1.5Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CO3_MOUSE C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates. Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. In chronic inflammation, acts as a chemoattractant for neutrophils (By similarity). It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes. The short isoform has B-cell stimulatory activity. Acts as a chemoattractant for neutrophils in chronic inflammation. Adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for C5AR2. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of C5AR2.

Publication Abstract from PubMed

The complement system is an intricate cascade of the innate immune system and plays a key role in microbial defense, inflammation, organ development, and tissue regeneration. There is increasing interest in developing complement regulatory and inhibitory agents to treat complement dysfunction. In this study, we describe the nanobody hC3Nb3, which is specific for the C-terminal C345c domain of human and mouse complement component C3/C3b/C3c and potently inhibits C3 cleavage by the alternative pathway. A high-resolution structure of the hC3Nb3-C345c complex explains how the nanobody blocks proconvertase assembly. Surprisingly, although the nanobody does not affect classical pathway-mediated C3 cleavage, hC3Nb3 inhibits classical pathway-driven hemolysis, suggesting that the C-terminal domain of C3b has an important function in classical pathway C5 convertase activity. The hC3Nb3 nanobody binds C3 with low nanomolar affinity in an SDS-resistant complex, and the nanobody is demonstrated to be a powerful reagent for C3 detection in immunohistochemistry and flow cytometry. Overall, the hC3Nb3 nanobody represents a potent inhibitor of both the alternative pathway and the terminal pathway, with possible applications in complement research, diagnostics, and therapeutics.

A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity.,Pedersen H, Jensen RK, Jensen JMB, Fox R, Pedersen DV, Olesen HG, Hansen AG, Christiansen D, Mazarakis SMM, Lojek N, Hansen P, Gadeberg TAF, Zarantonello A, Laursen NS, Mollnes TE, Johnson MB, Stevens B, Thiel S, Andersen GR J Immunol. 2020 Oct 15;205(8):2287-2300. doi: 10.4049/jimmunol.2000752. Epub 2020 , Sep 16. PMID:32938727^[1]

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

References

↑ Pedersen H, Jensen RK, Jensen JMB, Fox R, Pedersen DV, Olesen HG, Hansen AG, Christiansen D, Mazarakis SMM, Lojek N, Hansen P, Gadeberg TAF, Zarantonello A, Laursen NS, Mollnes TE, Johnson MB, Stevens B, Thiel S, Andersen GR. A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity. J Immunol. 2020 Oct 15;205(8):2287-2300. PMID:32938727 doi:10.4049/jimmunol.2000752