7AD6

Crystal structure of human complement C5 in complex with the K92 bovine knob domain peptide.

7AD6 の概要

• エントリーDOI: 10.2210/pdb7ad6/pdb
• 分子名称: Complement C5, K92 knob domain, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: complement c5, c5, ultralong, ultra-long, knob domain., immune system
• 由来する生物種: Bos taurus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 381631.24

構造登録者

Macpherson, A.,van den Elsen, J.M.H.,Schulze, M.E.,Birtley, J.R. (登録日: 2020-09-14, 公開日: 2021-03-10, 最終更新日: 2024-11-20)

主引用文献

Macpherson, A.,Laabei, M.,Ahdash, Z.,Graewert, M.A.,Birtley, J.R.,Schulze, M.E.,Crennell, S.,Robinson, S.A.,Holmes, B.,Oleinikovas, V.,Nilsson, P.H.,Snowden, J.,Ellis, V.,Mollnes, T.E.,Deane, C.M.,Svergun, D.,Lawson, A.D.,van den Elsen, J.M.
The allosteric modulation of Complement C5 by knob domain peptides.
Elife, 10:-, 2021

PubMed Abstract: Bovines have evolved a subset of antibodies with ultra-long heavy chain complementarity determining regions that harbour cysteine-rich knob domains. To produce high-affinity peptides, we previously isolated autonomous 3-6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 Å from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors, and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

PubMed: 33570492
DOI: 10.7554/eLife.63586

実験手法

X-RAY DIFFRACTION (2.75 Å)