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Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains.

ABSTRACT: 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.

SUBMITTER: McConnell JR

PROVIDER: S-EPMC8044635 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Using NMR to identify binding regions for N and C-terminal Hsp90 inhibitors using Hsp90 domains.

McConnell Jeanette R JR Dyson H Jane HJ McAlpine Shelli R SR

RSC medicinal chemistry 20210215 3

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 inhib ...[more]

PMID: 33898992

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