7B2P

Cryo-EM structure of complement C4b in complex with nanobody B5

7B2P の概要

• エントリーDOI: 10.2210/pdb7b2p/pdb
• 関連するPDBエントリー: 7B2M
• EMDBエントリー: 11988 11989
• 分子名称: Complement C4 beta chain, Complement C4 alpha chain, Complement C4 gamma chain, ... (6 entities in total)
• 機能のキーワード: complement, nanobody, c4b, inhibitor, complement classical pathway, nanobody-antigen complex, immune system
• 由来する生物種: Lama glama (Llama); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 205285.87

構造登録者

Oosterheert, W.,De la O Becerra, K.I.,Gros, P. (登録日: 2020-11-27, 公開日: 2022-03-02, 最終更新日: 2024-11-13)

主引用文献

De la O Becerra, K.I.,Oosterheert, W.,van den Bos, R.M.,Xenaki, K.T.,Lorent, J.H.,Ruyken, M.,Schouten, A.,Rooijakkers, S.H.M.,van Bergen En Henegouwen, P.M.P.,Gros, P.
Multifaceted Activities of Seven Nanobodies against Complement C4b.
J Immunol., 208:2207-2219, 2022

PubMed Abstract: Cleavage of the mammalian plasma protein C4 into C4b initiates opsonization, lysis, and clearance of microbes and damaged host cells by the classical and lectin pathways of the complement system. Dysregulated activation of C4 and other initial components of the classical pathway may cause or aggravate pathologies, such as systemic lupus erythematosus, Alzheimer disease, and schizophrenia. Modulating the activity of C4b by small-molecule or protein-based inhibitors may represent a promising therapeutic approach for preventing excessive inflammation and damage to host cells and tissue. Here, we present seven nanobodies, derived from llama () immunization, that bind to human C4b () with high affinities ranging from 3.2 nM to 14 pM. The activity of the nanobodies varies from no to complete inhibition of the classical pathway. The inhibiting nanobodies affect different steps in complement activation, in line with blocking sites for proconvertase formation, C3 substrate binding to the convertase, and regulator-mediated inactivation of C4b. For four nanobodies, we determined single-particle cryo-electron microscopy structures in complex with C4b at 3.4-4 Å resolution. The structures rationalize the observed functional effects of the nanobodies and define their mode of action during complement activation. Thus, we characterized seven anti-C4b nanobodies with diverse effects on the classical pathway of complement activation that may be explored for imaging, diagnostic, or therapeutic applications.

PubMed: 35428691
DOI: 10.4049/jimmunol.2100647

実験手法

ELECTRON MICROSCOPY (3.43 Å)