7HAD

PanDDA analysis group deposition -- Crystal structure of HSP90N in complex with Fr14363

これはPDB形式変換不可エントリーです。

7HAD の概要

• エントリーDOI: 10.2210/pdb7had/pdb
• Group deposition: Crystallographic fragment screening of Human heat shock protein 90 (G_1002298)
• 分子名称: Heat shock protein HSP 90-alpha, 2,3-dimethylbenzamide (3 entities in total)
• 機能のキーワード: crystallographic fragment screening; fragment-based drug discovery (fbdd); heat shock protein 90 (hsp90), chaperone
• 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: 27008.31

構造登録者

Huang, L.,Wang, W.,Zhu, Z.,Li, Q.,Li, M.,Zhou, H.,Xu, Q.,Wen, W.,Wang, Q.,Yu, F. (登録日: 2024-07-10, 公開日: 2025-03-26)

主引用文献

Huang, L.,Wang, W.,Zhu, Z.,Li, Q.,Li, M.,Zhou, H.,Xu, Q.,Wen, W.,Wang, Q.,Yu, F.
Novel starting points for fragment-based drug design against human heat-shock protein 90 identified using crystallographic fragment screening.
Iucrj, 12:177-187, 2025

PubMed Abstract: Heat-shock protein 90 (HSP90) is a highly active molecular chaperone that plays a crucial role in cellular function. It facilitates the folding, assembly and stability of various oncogenic proteins, particularly kinases and transcription factors involved in regulating tumor growth and maintenance signaling pathways. Consequently, HSP90 inhibitors are being explored as drugs for cancer therapy. Crystallographic fragment screening is a novel screening method that has been developed in recent years for fragment-based drug discovery and is known for its high hit rate and its ability to provide direct insights into the complex structures of proteins and compounds. In this paper, high-diffraction-resolution crystals of the N-terminal domain of human HSP90α were employed in crystallographic fragment screening to discover binding fragments and binding sites. A diverse library of 800 structurally distinct fragments was screened, yielding 91 starting points for the fragment-based drug design of new HSP90α N-terminal inhibitors. Nearly a thousand crystals were measured, with 738 being processed and phased using a highly automated data-processing pipeline including data reduction and phasing, refinement and hit identification via PanDDA multi-data-set analysis. The 91 identified compounds bind to eight distinct regions of the HSP90α N-terminus, with 63 fragments located in the ATP-binding pocket and its surroundings, thus demonstrating the potential for the development of HSP90α- and ATP-binding inhibitors. This study emphasizes crystallographic fragment screening as a powerful method that can effectively identify fragment molecules and inhibitors that bind to HSP90α, contributing to ongoing efforts in cancer drug discovery.

PubMed: 39819741
DOI: 10.1107/S2052252524012247

実験手法

X-RAY DIFFRACTION (1.59 Å)