6YSQ

The hC4Nb8 complement inhibitory nanobody in complex with C4b

Summary for 6YSQ

• Entry DOI: 10.2210/pdb6ysq/pdb
• Descriptor: Complement C4 beta chain, Complement C4-A alpha chain, Complement C4 gamma chain, ... (5 entities in total)
• Functional Keywords: nanobody, inhibitor, complement c4b, immune system
• Biological source: Escherichia coli; More
• Total number of polymer chains: 8
• Total formula weight: 392427.12

Authors

Zarantonello, A.,Laursen, N.S.,Andersen, G.R. (deposition date: 2020-04-23, release date: 2020-06-24, Last modification date: 2024-10-09)

Primary citation

Zarantonello, A.,Presumey, J.,Simoni, L.,Yalcin, E.,Fox, R.,Hansen, A.,Olesen, H.G.,Thiel, S.,Johnson, M.B.,Stevens, B.,Laursen, N.S.,Carroll, M.C.,Andersen, G.R.
An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase.
J Immunol., 205:1678-1694, 2020

PubMed Abstract: The classical and lectin pathways of the complement system are important for the elimination of pathogens and apoptotic cells and stimulation of the adaptive immune system. Upon activation of these pathways, complement component C4 is proteolytically cleaved, and the major product C4b is deposited on the activator, enabling assembly of a C3 convertase and downstream alternative pathway amplification. Although excessive activation of the lectin and classical pathways contributes to multiple autoimmune and inflammatory diseases and overexpression of a C4 isoform has recently been linked to schizophrenia, a C4 inhibitor and structural characterization of the convertase formed by C4b is lacking. In this study, we present the nanobody hC4Nb8 that binds with picomolar affinity to human C4b and potently inhibits in vitro complement C3 deposition through the classical and lectin pathways in human serum and in mouse serum. The crystal structure of the C4b:hC4Nb8 complex and a three-dimensional reconstruction of the C4bC2 proconvertase obtained by electron microscopy together rationalize how hC4Nb8 prevents proconvertase assembly through recognition of a neoepitope exposed in C4b and reveals a unique C2 conformation compared with the alternative pathway proconvertase. On human induced pluripotent stem cell-derived neurons, the nanobody prevents C3 deposition through the classical pathway. Furthermore, hC4Nb8 inhibits the classical pathway-mediated immune complex delivery to follicular dendritic cells in vivo. The hC4Nb8 represents a novel ultrahigh-affinity inhibitor of the classical and lectin pathways of the complement cascade under both in vitro and in vivo conditions.

PubMed: 32769120
DOI: 10.4049/jimmunol.2000528

Experimental method

X-RAY DIFFRACTION (3.3 Å)