7OP0

Crystal structure of complement C5 in complex with chemically synthesized K92 knob domain.

7OP0 の概要

• エントリーDOI: 10.2210/pdb7op0/pdb
• 分子名称: Complement C5 alpha chain, Complement C5 beta chain, K92chemFE, ... (6 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: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 190491.42

構造登録者

Macpherson, A.,van der Elsen, J.M.H.,Schulze, M.E.,Birtley, J.R. (登録日: 2021-05-28, 公開日: 2022-04-06, 最終更新日: 2024-11-06)

主引用文献

Macpherson, A.,Birtley, J.R.,Broadbridge, R.J.,Brady, K.,Schulze, M.E.D.,Tang, Y.,Joyce, C.,Saunders, K.,Bogle, G.,Horton, J.,Kelm, S.,Taylor, R.D.,Franklin, R.J.,Selby, M.D.,Laabei, M.,Wonfor, T.,Hold, A.,Stanley, P.,Vadysirisack, D.,Shi, J.,van den Elsen, J.,Lawson, A.D.G.
The Chemical Synthesis of Knob Domain Antibody Fragments.
Acs Chem.Biol., 16:1757-1769, 2021

PubMed Abstract: Cysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to a chemical synthesis, with a co-crystal structure of a chemically synthesized knob domain in complex with an antigen showing structural equivalence to the biological product. For drug discovery, following the immunization of cattle, knob domain peptides can be synthesized directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate nonbiological modifications. We demonstrate that, through rational design with non-natural amino acids, a paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclizations, exploiting the proximity of the N and C termini to synthesize functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains, together with the characterization of their molecular structures, in vitro pharmacology, and pharmacokinetics.

PubMed: 34406751
DOI: 10.1021/acschembio.1c00472

実験手法

X-RAY DIFFRACTION (2.57 Å)