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5in9

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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.

Structural highlights

5in9 is a 2 chain structure with sequence from Canis lupus familiaris. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.6Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ENPL_CANLF Molecular chaperone that functions in the processing and transport of secreted proteins. When associated with CNPY3, required for proper folding of Toll-like receptors. Functions in endoplasmic reticulum associated degradation (ERAD). Has ATPase activity (By similarity).

Publication Abstract from PubMed

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.

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold.,Crowley VM, Khandelwal A, Mishra S, Stothert AR, Huard DJ, Zhao J, Muth A, Duerfeldt AS, Kizziah JL, Lieberman RL, Dickey CA, Blagg BS J Med Chem. 2016 Apr 14;59(7):3471-88. doi: 10.1021/acs.jmedchem.6b00085. Epub, 2016 Apr 4. PMID:27003516^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Crowley VM, Khandelwal A, Mishra S, Stothert AR, Huard DJ, Zhao J, Muth A, Duerfeldt AS, Kizziah JL, Lieberman RL, Dickey CA, Blagg BS. Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold. J Med Chem. 2016 Apr 14;59(7):3471-88. doi: 10.1021/acs.jmedchem.6b00085. Epub, 2016 Apr 4. PMID:27003516 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00085