7FBP

FXIIa-cMCoFx1 complex

7FBP の概要

• エントリーDOI: 10.2210/pdb7fbp/pdb
• 分子名称: Coagulation factor XIIa light chain, cMCoFx1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: serine protease, inhibitor, macrocyclic peptide, cyclotide, blood clotting
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30738.48

構造登録者

Sengoku, T.,Liu, W.,de Veer, S.J.,Huang, Y.H.,Okada, C.,Zdenek, C.N.,Fry, B.G.,Swedberg, J.E.,Passioura, T.,Craik, D.J.,Suga, H.,Ogata, K. (登録日: 2021-07-12, 公開日: 2021-11-10, 最終更新日: 2024-10-30)

主引用文献

Liu, W.,de Veer, S.J.,Huang, Y.H.,Sengoku, T.,Okada, C.,Ogata, K.,Zdenek, C.N.,Fry, B.G.,Swedberg, J.E.,Passioura, T.,Craik, D.J.,Suga, H.
An Ultrapotent and Selective Cyclic Peptide Inhibitor of Human beta-Factor XIIa in a Cyclotide Scaffold.
J.Am.Chem.Soc., 143:18481-18489, 2021

PubMed Abstract: Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical diversity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10 members based on the cyclotide scaffold of trypsin inhibitor-II (MCoTI-II). The most potent and selective inhibitor, cMCoFx1, has a pM inhibitory constant toward FXIIa with greater than three orders of magnitude selectivity over related serine proteases, realizing specific inhibition of the intrinsic coagulation pathway. The cocrystal structure of cMCoFx1 and FXIIa revealed interactions at several positions across the contact interface that conveyed high affinity binding, highlighting that such cyclotides are attractive cystine knot scaffolds for therapeutic development.

PubMed: 34723512
DOI: 10.1021/jacs.1c07574

実験手法

X-RAY DIFFRACTION (1.99 Å)