6C91
Structure of GRP94 with a resorcinylic inhibitor.
Summary for 6C91
| Entry DOI | 10.2210/pdb6c91/pdb |
| Descriptor | Endoplasmin, SULFATE ION, 5-[2-(1-benzyl-1H-imidazol-2-yl)ethyl]-4,6-dichlorobenzene-1,3-diol, ... (5 entities in total) |
| Functional Keywords | chaperone, inhibitor, endoplasmin, chaperone-inhibitor complex, chaperone/inhibitor |
| Biological source | Canis lupus familiaris (Dog) More |
| Total number of polymer chains | 2 |
| Total formula weight | 54889.49 |
| Authors | Que, N.L.S.,Gewirth, D.T. (deposition date: 2018-01-25, 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 Cited by 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: 29528635DOI: 10.1021/acs.jmedchem.7b01608 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.895 Å) |
Structure validation
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