7eg4: Difference between revisions
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==== | ==Cryo-EM structure of nauclefine-induced PDE3A-SLFN12 complex== | ||
<StructureSection load='7eg4' size='340' side='right'caption='[[7eg4]]' scene=''> | <StructureSection load='7eg4' size='340' side='right'caption='[[7eg4]], [[Resolution|resolution]] 3.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7eg4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EG4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EG4 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=7eg4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eg4 OCA], [https://pdbe.org/7eg4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eg4 RCSB], [https://www.ebi.ac.uk/pdbsum/7eg4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eg4 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7eg4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eg4 OCA], [https://pdbe.org/7eg4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eg4 RCSB], [https://www.ebi.ac.uk/pdbsum/7eg4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eg4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/PDE3A_HUMAN PDE3A_HUMAN] Brachydactyly-arterial hypertension syndrome. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PDE3A_HUMAN PDE3A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[UniProtKB:Q9Z0X4] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Molecular glues are a class of small molecular drugs that mediate protein-protein interactions, that induce either the degradation or stabilization of target protein. A structurally diverse group of chemicals, including 17-beta-estradiol (E2), anagrelide, nauclefine, and DNMDP, induces apoptosis by forming complexes with phosphodiesterase 3A (PDE3A) and Schlafen 12 protein (SLFN12). They do so by binding to the PDE3A enzymatic pocket that allows the compound-bound PDE3A to recruit and stabilize SLFN12, which in turn blocks protein translation, leading to apoptosis. In this work, we report the high-resolution cryo-electron microscopy structure of PDE3A-SLFN12 complexes isolated from cultured HeLa cells pre-treated with either anagrelide, or nauclefine, or DNMDP. The PDE3A-SLFN12 complexes exhibit a butterfly-like shape, forming a heterotetramer with these small molecules, which are packed in a shallow pocket in the catalytic domain of PDE3A. The resulting small molecule-modified interface binds to the short helix (E552-I558) of SLFN12 through hydrophobic interactions, thus "gluing" the two proteins together. Based on the complex structure, we designed and synthesized analogs of anagrelide, a known drug used for the treatment of thrombocytosis, to enhance their interactions with SLFN12, and achieved superior efficacy in inducing apoptosis in cultured cells as well as in tumor xenografts. | |||
Structure of PDE3A-SLFN12 complex and structure-based design for a potent apoptosis inducer of tumor cells.,Chen J, Liu N, Huang Y, Wang Y, Sun Y, Wu Q, Li D, Gao S, Wang HW, Huang N, Qi X, Wang X Nat Commun. 2021 Oct 27;12(1):6204. doi: 10.1038/s41467-021-26546-8. PMID:34707099<ref>PMID:34707099</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7eg4" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Chen J]] | ||
[[Category: Liu N]] | |||
[[Category: Wang HW]] | |||
[[Category: Wang XD]] | |||