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| | ==TNNI3K complexed with inhibitor 2== | | ==TNNI3K complexed with inhibitor 2== |
| - | <StructureSection load='4yff' size='340' side='right' caption='[[4yff]], [[Resolution|resolution]] 3.07Å' scene=''> | + | <StructureSection load='4yff' size='340' side='right'caption='[[4yff]], [[Resolution|resolution]] 3.07Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4yff]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YFF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YFF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4yff]] 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=4YFF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YFF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4CV:3-[(5-BROMO-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)AMINO]-N-METHYL-4-(MORPHOLIN-4-YL)BENZENESULFONAMIDE'>4CV</scene></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]] 3.07Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4yfi|4yfi]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4CV:3-[(5-BROMO-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)AMINO]-N-METHYL-4-(MORPHOLIN-4-YL)BENZENESULFONAMIDE'>4CV</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TNNI3K, CARK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4yff FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yff OCA], [https://pdbe.org/4yff PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yff RCSB], [https://www.ebi.ac.uk/pdbsum/4yff PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yff ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4yff FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yff OCA], [http://pdbe.org/4yff PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yff RCSB], [http://www.ebi.ac.uk/pdbsum/4yff PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yff ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN]] The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN]] May play a role in cardiac physiology.<ref>PMID:12721663</ref> | + | [https://www.uniprot.org/uniprot/TNI3K_HUMAN TNI3K_HUMAN] May play a role in cardiac physiology.<ref>PMID:12721663</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.
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| - | Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).,Lawhorn BG, Philp J, Zhao Y, Louer C, Hammond M, Cheung M, Fries H, Graves AP, Shewchuk L, Wang L, Cottom JE, Qi H, Zhao H, Totoritis R, Zhang G, Schwartz B, Li H, Sweitzer S, Holt DA, Gatto GJ Jr, Kallander LS J Med Chem. 2015 Sep 24;58(18):7431-48. doi: 10.1021/acs.jmedchem.5b00931. Epub, 2015 Sep 10. PMID:26355916<ref>PMID:26355916</ref>
| + | ==See Also== |
| - | | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 4yff" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Lawhorn, B G]] | + | [[Category: Lawhorn BG]] |
| - | [[Category: Shewchuk, L M]] | + | [[Category: Shewchuk LM]] |
| - | [[Category: Wang, L]] | + | [[Category: Wang L]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
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