5IN9
Crystal structure of Grp94 bound to methyl 3-chloro-2-(2-(1-((5-chlorofuran-2-yl)methyl)-1H-imidazol-2-yl)ethyl)-4,6-dihydroxybenzoate, an inhibitor based on the BnIm and Radamide scaffolds.
Summary for 5IN9
| Entry DOI | 10.2210/pdb5in9/pdb |
| Descriptor | Endoplasmin, TRIETHYLENE GLYCOL, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | cation-pi interaction, bnim and radamide scaffold-based inhibitor, atp binding site, chaperone-inhibitor complex, chaperone/inhibitor |
| Biological source | Canis lupus familiaris (Dog) |
| Cellular location | Endoplasmic reticulum lumen: P41148 |
| Total number of polymer chains | 2 |
| Total formula weight | 54545.10 |
| Authors | Lieberman, R.L.,Huard, D.J.E.,Kizziah, J.L. (deposition date: 2016-03-07, release date: 2016-05-04, Last modification date: 2023-09-27) |
| Primary citation | Crowley, V.M.,Khandelwal, A.,Mishra, S.,Stothert, A.R.,Huard, D.J.,Zhao, J.,Muth, A.,Duerfeldt, A.S.,Kizziah, J.L.,Lieberman, R.L.,Dickey, C.A.,Blagg, B.S. Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold. J.Med.Chem., 59:3471-3488, 2016 Cited by PubMed Abstract: Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure-activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm. PubMed: 27003516DOI: 10.1021/acs.jmedchem.6b00085 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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