6gfa

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

spinqualitylabelsall models 6gfa, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gfa is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ATP, MG Gene: HSPH1, HSP105, HSP110, KIAA0201 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HS105_HUMAN] Acts as a nucleotide-exchange factor (NEF) for chaperone proteins HSPA1A and HSPA1B, promoting the release of ADP from HSPA1A/B thereby triggering client/substrate protein release (PubMed:24318877). Prevents the aggregation of denatured proteins in cells under severe stress, on which the ATP levels decrease markedly. Inhibits HSPA8/HSC70 ATPase and chaperone activities (By similarity).[UniProtKB:Q60446][UniProtKB:Q61699] Publication Abstract from PubMed 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. Selecting the first chemical molecule inhibitor of HSP110 for colorectal cancer therapy.,Gozzi GJ, Gonzalez D, Boudesco C, Dias AMM, Gotthard G, Uyanik B, Dondaine L, Marcion G, Hermetet F, Denis C, Hardy L, Suzanne P, Douhard R, Jego G, Dubrez L, Demidov ON, Neiers F, Briand L, Sopkova-de Oliveira Santos J, Voisin-Chiret AS, Garrido C Cell Death Differ. 2019 May 8. pii: 10.1038/s41418-019-0343-4. doi:, 10.1038/s41418-019-0343-4. PMID:31068676 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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