6xkd: Difference between revisions

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 ==Structure of ligand-bound mouse cGAMP hydrolase ENPP1==
-<StructureSection load='6xkd' size='340' side='right'caption='[[6xkd]]' scene=''>
+<StructureSection load='6xkd' size='340' side='right'caption='[[6xkd]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XKD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XKD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6xkd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XKD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XKD FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6xkd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xkd OCA], [https://pdbe.org/6xkd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xkd RCSB], [https://www.ebi.ac.uk/pdbsum/6xkd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xkd ProSAT]</span></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IJE:{2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl}phosphonic+acid'>IJE</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6xkd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xkd OCA], [https://pdbe.org/6xkd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xkd RCSB], [https://www.ebi.ac.uk/pdbsum/6xkd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xkd ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[https://www.uniprot.org/uniprot/ENPP1_MOUSE ENPP1_MOUSE] Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments.<ref>PMID:9662402</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/ENPP1_MOUSE ENPP1_MOUSE] Appears to modulate insulin sensitivity (By similarity). By generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling.<ref>PMID:1647027</ref> <ref>PMID:9662402</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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 Ki &lt; 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.
+Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP.,Carozza JA, Brown JA, Bohnert V, Fernandez D, AlSaif Y, Mardjuki RE, Smith M, Li L Cell Chem Biol. 2020 Nov 19;27(11):1347-1358.e5. doi:, 10.1016/j.chembiol.2020.07.007. Epub 2020 Jul 28. PMID:32726585<ref>PMID:32726585</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6xkd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures|Ectonucleotide pyrophosphatase/phosphodiesterase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Mus musculus]]
 [[Category: Fernandez D]]
 [[Category: Li L]]