PDBsum entry 4l94

Chaperone/chaperone inhibitor

PDB id: 4l94

Contents

Protein chain

207 a.a.

Ligands

S46

Waters ×178

PDB id:

4l94

Name:

Chaperone/chaperone inhibitor

Title:

Crystal structure of human hsp90 with s46

Structure:

Heat shock protein hsp 90-alpha. Chain: a. Fragment: unp residues 9-236. Synonym: heat shock 86 kda, hsp 86, hsp86, renal carcinoma antigen ny-ren-38. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hsp90aa1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.65Å R-factor: 0.193 R-free: 0.214

Authors:

J.Li,J.Ren,M.Yang,B.Xiong,J.He

Key ref:

J.Ren et al. (2014). Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization. Bioorg Med Chem Lett, 24, 2525-2529. PubMed id: 24751441 DOI: 10.1016/j.bmcl.2014.03.100

Date:

18-Jun-13 Release date: 18-Jun-14

Protein chain

P07900  (HS90A_HUMAN) -  Heat shock protein HSP 90-alpha from Homo sapiens

Seq: 732 a.a.

Struc: 207 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.4.10 - non-chaperonin molecular chaperone ATPase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmcl.2014.03.100

Bioorg Med Chem Lett 24:2525-2529 (2014)

PubMed id: 24751441

Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization.

J.Ren, J.Li, Y.Wang, W.Chen, A.Shen, H.Liu, D.Chen, D.Cao, Y.Li, N.Zhang, Y.Xu, M.Geng, J.He, B.Xiong, J.Shen.

ABSTRACT

Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20-40 nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs.