13DW

Structure of HSP90b bound to de-novo designed binder H2

Summary for 13DW

• Entry DOI: 10.2210/pdb13dw/pdb
• EMDB information: 77013
• Descriptor: Heat shock protein HSP 90-beta, De-novo designed binder H2, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (4 entities in total)
• Functional Keywords: hsp90, de-novo designed binder, chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 197893.96

Authors

Srivastava, D.,Singh, S.,Artemyev, N.O. (deposition date: 2026-05-01, release date: 2026-10-28)

Primary citation

Srivastava, D.,Singh, S.,Boyd, K.,Artemyev, N.O.
Structural analysis of de novo-designed binders targeting the closed state of HSP90.
Structure, 2026

PubMed Abstract: Heat shock protein 90 (HSP90) assists the folding and maturation of numerous signaling proteins and is an important therapeutic target. Most HSP90 inhibitors target the ATP-binding pocket and disrupt ATP-induced closure, whereas inhibitors targeting the closed state have not been developed. Here, we report de novo-designed protein binders that selectively recognize closed HSP90. Two binders, H2 and H4, have similar folds and affinities for HSP90 but distinct binding kinetics. Cryo-EM structures of HSP90 complexes with H2 and H4 revealed high accuracy of the BindCraft predictions. H2 and H4 compete with p23 at one, but not both, symmetrical p23-binding sites. In HEK293T cells, H2 induced a reduced heat shock response compared with the ATP-site inhibitor 17-DMAG while reducing levels of CDK4, providing functional evidence for HSP90 inhibition. These binders provide tools for probing HSP90 function and potential leads for developing closed-state HSP90 inhibitors.

PubMed: 42887492
DOI: 10.1016/j.str.2026.09.007

Experimental method

ELECTRON MICROSCOPY (2.9 Å)