6XKD
Structure of ligand-bound mouse cGAMP hydrolase ENPP1
Summary for 6XKD
| Entry DOI | 10.2210/pdb6xkd/pdb |
| Descriptor | Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total) |
| Functional Keywords | hydrolase, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 191818.79 |
| Authors | Fernandez, D.,Li, L. (deposition date: 2020-06-26, release date: 2021-06-02, Last modification date: 2024-10-23) |
| Primary citation | Carozza, J.A.,Brown, J.A.,Bohnert, V.,Fernandez, D.,AlSaif, Y.,Mardjuki, R.E.,Smith, M.,Li, L. Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP. Cell Chem Biol, 27:1347-1358.e5, 2020 Cited by PubMed Abstract: Cancer cells initiate an innate immune response by synthesizing and exporting the small-molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small-molecule ENPP1 inhibitors are much needed as tools to study the basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. In addition, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class inhibitors with K < 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics. PubMed: 32726585DOI: 10.1016/j.chembiol.2020.07.007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.2 Å) |
Structure validation
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