6CEO

Structure of Hsp90 NTD with a GRP94-selective resorcinylic inhibitor.

Summary for 6CEO

• Entry DOI: 10.2210/pdb6ceo/pdb
• Descriptor: Heat shock protein HSP 90-alpha, dimethyl 2-[2-(1-benzyl-1H-imidazol-2-yl)ethyl]-4,6-dihydroxybenzene-1,3-dicarboxylate, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: chaperone, inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 29391.46

Authors

Que, N.L.S.,Gewirth, D.T. (deposition date: 2018-02-12, release date: 2018-04-18, Last modification date: 2024-03-13)

Primary citation

Que, N.L.S.,Crowley, V.M.,Duerfeldt, A.S.,Zhao, J.,Kent, C.N.,Blagg, B.S.J.,Gewirth, D.T.
Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.
J. Med. Chem., 61:2793-2805, 2018

PubMed Abstract: Grp94 and Hsp90, the ER and cytoplasmic hsp90 paralogs, share a conserved ATP-binding pocket that has been targeted for therapeutics. Paralog-selective inhibitors may lead to drugs with fewer side effects. Here, we analyzed 1 (BnIm), a benzyl imidazole resorcinylic inhibitor, for its mode of binding. The structures of 1 bound to Hsp90 and Grp94 reveal large conformational changes in Grp94 but not Hsp90 that expose site 2, a binding pocket adjacent to the central ATP cavity that is ordinarily blocked. The Grp94:1 structure reveals a flipped pose of the resorcinylic scaffold that inserts into the exposed site 2. We exploited this flipped binding pose to develop a Grp94-selective derivative of 1. Our structural analysis shows that the ability of the ligand to insert its benzyl imidazole substituent into site 1, a different side pocket off the ATP binding cavity, is the key to exposing site 2 in Grp94.

PubMed: 29528635
DOI: 10.1021/acs.jmedchem.7b01608

Experimental method

X-RAY DIFFRACTION (1.896 Å)