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5vt1
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==Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor== | ==Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor== | ||
| - | <StructureSection load='5vt1' size='340' side='right' caption='[[5vt1]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='5vt1' size='340' side='right'caption='[[5vt1]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5vt1]] is a 1 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[5vt1]] is a 1 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=5VT1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VT1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9JS:4-({5-[(3-HYDROXY-4-METHYLPHENYL)AMINO]-4-OXO-4H-1,2,6-THIADIAZIN-3-YL}AMINO)BENZAMIDE'>9JS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9JS:4-({5-[(3-HYDROXY-4-METHYLPHENYL)AMINO]-4-OXO-4H-1,2,6-THIADIAZIN-3-YL}AMINO)BENZAMIDE'>9JS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5vt1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vt1 OCA], [https://pdbe.org/5vt1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vt1 RCSB], [https://www.ebi.ac.uk/pdbsum/5vt1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vt1 ProSAT]</span></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/KKCC2_HUMAN KKCC2_HUMAN] Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Isoform 1, isoform 2 and isoform 3 phosphorylate CAMK1 and CAMK4. Isoform 3 phosphorylates CAMK1D. Isoform 4, isoform 5 and isoform 6 lacking part of the calmodulin-binding domain are inactive. Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca(2+) signals (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). May play a role in neurite growth. Isoform 3 may promote neurite elongation, while isoform 1 may promoter neurite branching.<ref>PMID:11395482</ref> <ref>PMID:12935886</ref> <ref>PMID:9662074</ref> <ref>PMID:21957496</ref> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors. | ||
| + | |||
| + | 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.,Asquith CRM, Godoi PH, Counago RM, Laitinen T, Scott JW, Langendorf CG, Oakhill JS, Drewry DH, Zuercher WJ, Koutentis PA, Willson TM, Kalogirou AS Molecules. 2018 May 19;23(5). pii: molecules23051221. doi:, 10.3390/molecules23051221. PMID:29783765<ref>PMID:29783765</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5vt1" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Calcium/calmodulin-dependent protein kinase kinase|Calcium/calmodulin-dependent protein kinase kinase]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: Arruda | + | [[Category: Arruda P]] |
| - | [[Category: Asquith | + | [[Category: Asquith CRM]] |
| - | [[Category: Counago | + | [[Category: Counago RM]] |
| - | [[Category: Edwards | + | [[Category: Edwards AM]] |
| - | [[Category: Gileadi | + | [[Category: Gileadi O]] |
| - | [[Category: Kalogirou | + | [[Category: Kalogirou AS]] |
| - | [[Category: Koutentis | + | [[Category: Koutentis PA]] |
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Current revision
Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor
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