8AGJ

Structure of human Heat shock protein 90-alpha N-terminal domain (Hsp90-NTD) variant K112A in complex with JMC31

8AGJ の概要

• エントリーDOI: 10.2210/pdb8agj/pdb
• 関連するPDBエントリー: 8AGI
• 分子名称: Heat shock protein HSP 90-alpha, 1-[2,4-bis(oxidanyl)-5-propan-2-yl-phenyl]-5-[4-[(cyclohexylmethylamino)methyl]phenyl]-~{N}-ethyl-1,2,3-triazole-4-carboxamide (3 entities in total)
• 機能のキーワード: hsp90, ntd, k112a, 1, 2, 3-triazole-based compound, complex, chaperone
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58413.34

構造登録者

Tassone, G.,Pozzi, C.,Mazzorana, M.,Mangani, S.,Maramai, S. (登録日: 2022-07-20, 公開日: 2022-09-07, 最終更新日: 2024-01-31)

主引用文献

Tassone, G.,Mazzorana, M.,Mangani, S.,Petricci, E.,Cini, E.,Giannini, G.,Pozzi, C.,Maramai, S.
Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that stabilizes client proteins in a folded and functional state. It is composed of two identical and symmetrical subunits and each monomer consists of three domains, the N-terminal (NTD), the middle (MD), and the C-terminal domain (CTD). Since the chaperone activity requires ATP hydrolysis, molecules able to occupy the ATP-binding pocket in the NTD act as Hsp90 inhibitors, leading to client protein degradation and cell death. Therefore, human Hsp90 represents a validated target for developing new anticancer drugs. Since protozoan parasites use their Hsp90 to trigger important transitions between different stages of their life cycle, this protein also represents a profitable target in anti-parasite drug discovery. Nevertheless, the development of molecules able to selectively target the ATP-binding site of protozoan Hsp90 is challenging due to the high homology with the human Hsp90 NTD (hHsp90-NTD). In a previous work, a series of potent Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold was developed. The most promising inhibitor of the series, JMC31, showed potent Hsp90 binding and antiproliferative activity in NCI-H460 cells in the low-nanomolar range. In this work, we present the structural characterization of hHsp90-NTD in complex with JMC31 through X-ray crystallography. In addition, to elucidate the role of residue 112 on the ligand binding and its exploitability for the development of selective inhibitors, we investigated the crystal structures of hHsp90-NTD variants (K112R and K112A) in complex with JMC31.

PubMed: 36012721
DOI: 10.3390/ijms23169458

実験手法

X-RAY DIFFRACTION (2.32 Å)