9PMW

Structure of HTTQ23-HAP40 complex bound to macrocycles HHL1, HD4 and HL2

9PMW の概要

• エントリーDOI: 10.2210/pdb9pmw/pdb
• EMDBエントリー: 71743
• 分子名称: HHL1, HD4, HL2, ... (5 entities in total)
• 機能のキーワード: huntingtin, macrocycles, polyglutamine expansion, peptide binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 396814.65

構造登録者

Balakrishnan, S.,Deme, J.,Lea, S.M.,Harding, R.J. (登録日: 2025-07-18, 公開日: 2025-08-20, 最終更新日: 2025-10-15)

主引用文献

Wolf, E.,Fanti, R.,Ikenoue, T.,Deme, J.C.,Balakrishnan, S.,Keith, B.A.,Alteen, M.G.,Chandrasekaran, R.,Yadav, M.,Bhajiawala, R.,Ackloo, S.,Feng, J.,Pouladi, M.A.,Edwards, A.M.,Wilson, D.,Lea, S.M.,Suga, H.,Harding, R.J.
High-Affinity, Structure-Validated and Selective Macrocyclic Peptide Tools for Chemical Biology Studies of Huntingtin.
Biorxiv, 2025

PubMed Abstract: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the () gene, with no disease-modifying therapies currently available. The precise molecular function of the HTT protein is unclear, and the lack of selective chemical tools has limited functional studies. We have identified and characterized macrocyclic peptide binders targeting HTT. These binders exhibit low-nanomolar affinity and engage distinct HTT and HTT-HAP40 interfaces, as revealed by hydrogen-deuterium exchange mass spectrometry and cryo-electron microscopy. Chemoproteomics confirmed selective binding in cell extracts from wildtype but not HTT-null cell lines. HAP40 consistently and stoichiometrically co-purified with HTT across cell lines, including with HTT variants containing different CAG repeat lengths, highlighting the broad presence of the HTT-HAP40 complex.

PubMed: 41030958
DOI: 10.1101/2025.08.06.668955

実験手法

ELECTRON MICROSCOPY (2.1 Å)