4H5N

HSC70 NBD with PO4, Na, Cl

4H5N の概要

• エントリーDOI: 10.2210/pdb4h5n/pdb
• 関連するPDBエントリー: 4H5R 4H5T 4H5V 4H5W
• 分子名称: Heat shock cognate 71 kDa protein, PHOSPHATE ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: nucleotide binding domain, transcription
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P11142
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85861.24

構造登録者

Stec, B. (登録日: 2012-09-18, 公開日: 2014-03-19, 最終更新日: 2023-09-20)

主引用文献

Zhang, Z.,Cellitti, J.,Teriete, P.,Pellecchia, M.,Stec, B.
New crystal structures of HSC-70 ATP binding domain confirm the role of individual binding pockets and suggest a new method of inhibition.
Biochimie, 108:186-192, 2015

PubMed Abstract: In recent years the chaperone HSC-70 has become a target for drug design with a strong focus in anticancer therapies. In our study of possible inhibitors of HSC-70 enzymatic activity we screened compounds by NMR as well as X-ray crystallography. As part of our screening efforts we crystallized the human HSC-70 ATP binding domain and obtained novel crystal forms in addition to known structures. The new crystal structures highlight the mobility of the entire domain previously described by NMR, which was linked to its chaperone activity but not yet demonstrated by X-ray crystallography. Conformational changes across the entire molecule have been elucidated in response to the binding of small molecule ligands and show a pattern of mobility consistent with postulated signal transduction modes between the nucleotide binding domain (NBD) and the substrate binding domain (SBD). In addition, two crystal structures contained glycerol bound at a new site. Binding studies performed with glycerol analogs proved inhibitory properties of the site, which were further characterized by isothermal calorimetry and in silico docking studies. The presence of two binding pockets enabled us to explore a novel method of inhibition by compounds that bridge the adjacent phosphate and glycerol binding sites. Finally, an example of such a bridged inhibitor is proposed.

PubMed: 25433210
DOI: 10.1016/j.biochi.2014.11.012

実験手法

X-RAY DIFFRACTION (1.86 Å)