6GFA

Structure of Nucleotide binding domain of HSP110, ATP and Mg2+ complexed

6GFA の概要

• エントリーDOI: 10.2210/pdb6gfa/pdb
• 分子名称: Heat shock protein 105 kDa, MAGNESIUM ION, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: hsp110, hsp110de9, nucleotide-binding domain, hsph1, hsp105, 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: 42750.42

構造登録者

Gonzalez, D.,Gotthard, G.,Gozzi, G.J.,Seigneuric, R.,Neiers, F.,Briand, L.,Garrido, C. (登録日: 2018-04-29, 公開日: 2019-05-08, 最終更新日: 2024-01-17)

主引用文献

Gozzi, G.J.,Gonzalez, D.,Boudesco, C.,Dias, A.M.M.,Gotthard, G.,Uyanik, B.,Dondaine, L.,Marcion, G.,Hermetet, F.,Denis, C.,Hardy, L.,Suzanne, P.,Douhard, R.,Jego, G.,Dubrez, L.,Demidov, O.N.,Neiers, F.,Briand, L.,Sopkova-de Oliveira Santos, J.,Voisin-Chiret, A.S.,Garrido, C.
Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy.
Cell Death Differ., 27:117-129, 2020

PubMed Abstract: Pro-survival stress-inducible chaperone HSP110 is the only HSP for which a mutation has been found in a cancer. Multicenter clinical studies demonstrated a direct association between HSP110 inactivating mutation presence and excellent prognosis in colorectal cancer patients. Here, we have combined crystallographic studies on human HSP110 and in silico modeling to identify HSP110 inhibitors that could be used in colorectal cancer therapy. Two molecules (foldamers 33 and 52), binding to the same cleft of HSP110 nucleotide-binding domain, were selected from a chemical library (by co-immunoprecipitation, AlphaScreening, Interference-Biolayer, Duo-link). These molecules block HSP110 chaperone anti-aggregation activity and HSP110 association to its client protein STAT3, thereby inhibiting STAT3 phosphorylation and colorectal cancer cell growth. These effects were strongly decreased in HSP110 knockdown cells. Foldamer's 33 ability to inhibit tumor growth was confirmed in two colorectal cancer animal models. Although tumor cell death (apoptosis) was noted after treatment of the animals with foldamer 33, no apparent toxicity was observed, notably in epithelial cells from intestinal crypts. Taken together, we identified the first HSP110 inhibitor, a possible drug-candidate for colorectal cancer patients whose unfavorable outcome is associated to HSP110.

PubMed: 31068676
DOI: 10.1038/s41418-019-0343-4

実験手法

X-RAY DIFFRACTION (2 Å)