8fe5: Difference between revisions

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-'''Unreleased structure'''
-The entry 8fe5 is ON HOLD
+==Structure of J-PKAc chimera complexed with Aplithianine B==
+<StructureSection load='8fe5' size='340' side='right'caption='[[8fe5]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8fe5]] 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=8FE5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FE5 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.51&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=XTT:6-[6-(3-methylimidazol-4-yl)-2,3-dihydro-1,4-thiazin-4-yl]-7,9-dihydropurin-8-one'>XTT</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=8fe5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fe5 OCA], [https://pdbe.org/8fe5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fe5 RCSB], [https://www.ebi.ac.uk/pdbsum/8fe5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fe5 ProSAT]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcalpha, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcalpha catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an Aplidium sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A (1) and B (2). Aplithianine A (1) showed potent inhibition against J-PKAcalpha with an IC(50) of approximately 1 muM in the primary screening assay. In kinome screening, 1 inhibited wild-type PKA with an IC(50) of 84 nM. Further mechanistic studies including cocrystallization and X-ray diffraction experiments revealed that 1 inhibited PKAcalpha catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC(50) values in the range approximately 11-90 nM. An efficient, four-step total synthesis of 1 has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors.
-Authors: Du, L., Wilson, B.A.P., Li, N., Martinez Fiesco, J.A., Dalilian, M., Wang, D., Smith, E.A., Wamiru, A., Goncharova, E.I., Zhang, P., O''Keefe, B.R.
+Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.,Du L, Wilson BAP, Li N, Shah R, Dalilian M, Wang D, Smith EA, Wamiru A, Goncharova EI, Zhang P, O'Keefe BR J Nat Prod. 2023 Oct 27;86(10):2283-2293. doi: 10.1021/acs.jnatprod.3c00394. Epub , 2023 Oct 16. PMID:37843072<ref>PMID:37843072</ref>
-Description: Structure of J-PKAc chimera complexed with Aplithianine B
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Martinez Fiesco, J.A]]
+<div class="pdbe-citations 8fe5" style="background-color:#fffaf0;"></div>
-[[Category: Zhang, P]]
+== References ==
-[[Category: Wang, D]]
+<references/>
-[[Category: Dalilian, M]]
+__TOC__
-[[Category: Goncharova, E.I]]
+</StructureSection>
-[[Category: Wamiru, A]]
+[[Category: Homo sapiens]]
-[[Category: Wilson, B.A.P]]
+[[Category: Large Structures]]
-[[Category: Du, L]]
+[[Category: Dalilian M]]
-[[Category: O''Keefe, B.R]]
+[[Category: Du L]]
-[[Category: Li, N]]
+[[Category: Goncharova EI]]
-[[Category: Smith, E.A]]
+[[Category: Li N]]
+[[Category: Martinez Fiesco JA]]
+[[Category: O'Keefe BR]]
+[[Category: Smith EA]]
+[[Category: Wamiru A]]
+[[Category: Wang D]]
+[[Category: Wilson BAP]]
+[[Category: Zhang P]]