8de6 | pdb_00008de6

Oligomeric C9 in complex with aE11 Fab

spinqualitylabelsall models 8de6, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8de6 is a 7 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, CA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CO9_HUMAN Age-related macular degeneration;Immunodeficiency due to a late component of complements deficiency. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Function CO9_HUMAN Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C9 is the pore-forming subunit of the MAC. Publication Abstract from PubMed The Membrane Attack Complex (MAC) is responsible for forming large beta-barrel channels in the membranes of pathogens, such as gram-negative bacteria. Off-target MAC assembly on endogenous tissue is associated with inflammatory diseases and cancer. Accordingly, a human C5b-9 specific antibody, aE11, has been developed that detects a neoepitope exposed in C9 when it is incorporated into the C5b-9 complex, but not present in the plasma native C9. For nearly four decades aE11 has been routinely used to study complement, MAC-related inflammation, and pathophysiology. However, the identity of C9 neoepitope remains unknown. Here, we determined the cryo-EM structure of aE11 in complex with polyC9 at 3.2 A resolution. The aE11 binding site is formed by two separate surfaces of the oligomeric C9 periphery and is therefore a discontinuous quaternary epitope. These surfaces are contributed by portions of the adjacent TSP1, LDLRA, and MACPF domains of two neighbouring C9 protomers. By substituting key antibody interacting residues to the murine orthologue, we validated the unusual binding modality of aE11. Furthermore, aE11 can recognise a partial epitope in purified monomeric C9 in vitro, albeit weakly. Taken together, our results reveal the structural basis for MAC recognition by aE11. The neoepitope of the complement C5b-9 Membrane Attack Complex is formed by proximity of adjacent ancillary regions of C9.,Bayly-Jones C, Ho BHT, Lau C, Leung EWW, D'Andrea L, Lupton CJ, Ekkel SM, Venugopal H, Whisstock JC, Mollnes TE, Spicer BA, Dunstone MA Commun Biol. 2023 Jan 13;6(1):42. doi: 10.1038/s42003-023-04431-y. PMID:36639734 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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