9IGA

Beta-hairpin macrocyclic peptide in complex with STAT1

9IGA の概要

• エントリーDOI: 10.2210/pdb9iga/pdb
• 分子名称: Isoform Alpha of Signal transducer and activator of transcription 1-alpha/beta, OPG024 protein, ORTHO-XYLENE (3 entities in total)
• 機能のキーワード: stat1, 018, poxvirus, transcription
• 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: 66540.43

構造登録者

Pantelejevs, T. (登録日: 2025-02-19, 公開日: 2026-02-18)

主引用文献

Bula, A.L.,Bobrovs, R.,Arsenyan, P.,Pantelejevs, T.
Consequences of Peptide Macrocyclization Revealed by Virus-Inspired beta-Hairpin Mimetics.
Acs Chem.Biol., 21:160-169, 2026

PubMed Abstract: Mimicry of protein secondary structure elements, such as α-helices and β-sheets, using conformationally constrained peptide macrocycles, can be utilized to disrupt native protein-protein and protein-nucleic acid interactions. Although α-helical stapled peptides have been extensively studied as pharmacological probes, the application of β-sheet and β-hairpin mimetics remains comparatively limited. Less is known about the structural and biophysical consequences of β-hairpin macrocyclization in the context of target binding. In this work, we use a poxvirus immune antagonist protein 018 as a template for the structure-based design of β-hairpin mimetic macrocyclic peptides targeting the STAT1 transcription factor. We demonstrate that successive orthogonal cyclizations have additive effects on the thermodynamic and kinetic properties of peptide binding, most notably slowing the dissociation from the target. We elucidate the structural and dynamic consequences of interstrand and head-to-tail cross-linking and propose a kinetic model explaining the gains in target residence. Finally, we highlight the pharmacological potential of these peptides by competitive inhibition of STAT1 binding to its cognate interferon receptor docking site. These data suggest that β-hairpin macrocyclization may represent a general strategy to extend target engagement, with implications for peptidic probe design.

PubMed: 41427528
DOI: 10.1021/acschembio.5c00834

実験手法

X-RAY DIFFRACTION (2.8 Å)