6L63

Human Coagulation Factor XIIa (FXIIa) bound with the macrocyclic peptide F3 containing two (1S,2S)-2-ACHC residues

Summary for 6L63

• Entry DOI: 10.2210/pdb6l63/pdb
• Related PRD ID: PRD_900017
• Descriptor: Coagulation factor XII, F3, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: enzyme, blood clotting
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 57925.96

Authors

Sengoku, T.,Katoh, T.,Hirata, K.,Suga, H.,Ogata, K. (deposition date: 2019-10-26, release date: 2020-09-02, Last modification date: 2025-09-17)

Primary citation

Katoh, T.,Sengoku, T.,Hirata, K.,Ogata, K.,Suga, H.
Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic beta-amino acids.
Nat.Chem., 12:1081-1088, 2020

PubMed Abstract: Peptides that contain β-amino acids display stable secondary structures, such as helices and sheets, and are often referred to as foldamers. Cyclic β-amino acids (cβAAs), such as 2-aminocyclohexanecarboxylic acid (2-ACHC), are strong helix/turn inducers due to their restricted conformations. Here we report the ribosomal synthesis of foldamer peptides that contain multiple, up to ten, consecutive cβAAs via genetic code reprogramming. We also report the de novo discovery of macrocyclic cβAA-containing peptides capable of binding to a protein target. As a demonstration, potent binders with low-to-subnanomolar K values were identified for human factor XIIa (hFXIIa) and interferon-gamma receptor 1, from a library of their 10 members. One of the anti-hFXIIa macrocyclic peptides that exhibited a high inhibitory activity and serum stability was co-crystallized with hFXIIa. The X-ray structure revealed that it adopts an antiparallel β-sheet structure induced by a (1S,2S)-2-ACHC residue via the formation of two γ-turns. This work demonstrates the potential of this platform to explore the previously inaccessible sequence space of cβAA-containing peptides.

PubMed: 32839601
DOI: 10.1038/s41557-020-0525-1

Experimental method

X-RAY DIFFRACTION (3 Å)