2NC9

Apo solution structure of Hop TPR2A

2NC9 の概要

• エントリーDOI: 10.2210/pdb2nc9/pdb
• NMR情報: BMRB: 26011
• 分子名称: Stress-induced-phosphoprotein 1 (1 entity in total)
• 機能のキーワード: chaperone, heat-shock, hsp90, tpr
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15569.57

構造登録者

Darby, J.F.,Vidler, L.R.,Simpson, P.J.,Matthews, S.J.,Sharp, S.Y.,Pearl, L.H.,Hoelder, S.,Workman, P. (登録日: 2016-03-23, 公開日: 2017-03-29, 最終更新日: 2024-05-01)

主引用文献

Darby, J.F.,Vidler, L.R.,Simpson, P.J.,Al-Lazikani, B.,Matthews, S.J.,Sharp, S.Y.,Pearl, L.H.,Hoelder, S.,Workman, P.
Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches.
Sci Rep, 10:16000-16000, 2020

PubMed Abstract: Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native 'carboxylate clamp' interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping H-N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors.

PubMed: 32994435
DOI: 10.1038/s41598-020-71969-w

実験手法

SOLUTION NMR