Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains
| Autor: | Jeanette R. McConnell, H. Jane Dyson, Shelli R. McAlpine |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Allosteric regulation Binding pocket Pharmaceutical Science Crystal structure 01 natural sciences Biochemistry 03 medical and health sciences Heat shock protein Drug Discovery medicine Novobiocin 030304 developmental biology Pharmacology 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry Hsp90 0104 chemical sciences biology.protein Molecular Medicine Linker Binding domain medicine.drug |
| Zdroj: | RSC Med Chem |
| ISSN: | 2632-8682 |
| Popis: | We present the first NMR study of the interaction between heat shock protein 90 (Hsp90) and amino (N)-terminal inhibitors 17-AAG, and AUY922, and carboxy (C)-terminal modulators SM253, and LB51. We show that the two ATP mimics, 17-AAG and AUY922, bind deeply within the ATP binding pocket of the N-terminal domain, consistent with the crystal structures. In contrast, SM253, a C-terminal Hsp90 modulator, binds to the linker region between the N and middle domains. We also show that C-terminal inhibitor LB51 binds to the C-terminus with a more significant spectroscopic change than previously reported using NMR binding studies of C-terminal inhibitors novobiocin and silybin. These data provide key insights into how the allosteric inhibitor SM253 controls the C-terminal co-chaperones and confirms the binding domain of LB51. |
| Databáze: | OpenAIRE |
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