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| | <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 [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VT1 FirstGlance]. <br> | + | <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> | + | </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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CAMKK2, CAMKKB, KIAA0787 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </span></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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5vt1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vt1 OCA], [http://pdbe.org/5vt1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vt1 RCSB], [http://www.ebi.ac.uk/pdbsum/5vt1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vt1 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Calcium/calmodulin-dependent protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arruda, P]] | + | [[Category: Arruda P]] |
| - | [[Category: Asquith, C R.M]] | + | [[Category: Asquith CRM]] |
| - | [[Category: Counago, R M]] | + | [[Category: Counago RM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Gileadi O]] |
| - | [[Category: Kalogirou, A S]] | + | [[Category: Kalogirou AS]] |
| - | [[Category: Koutentis, P A]] | + | [[Category: Koutentis PA]] |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Protein kinase domain]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hsu LS, Chen GD, Lee LS, Chi CW, Cheng JF, Chen JY. Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity. J Biol Chem. 2001 Aug 17;276(33):31113-23. Epub 2001 Jun 6. PMID:11395482 doi:http://dx.doi.org/10.1074/jbc.M011720200
- ↑ Ishikawa Y, Tokumitsu H, Inuzuka H, Murata-Hori M, Hosoya H, Kobayashi R. Identification and characterization of novel components of a Ca2+/calmodulin-dependent protein kinase cascade in HeLa cells. FEBS Lett. 2003 Aug 28;550(1-3):57-63. PMID:12935886
- ↑ Hsu LS, Tsou AP, Chi CW, Lee CH, Chen JY. Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase. J Biomed Sci. 1998;5(2):141-9. PMID:9662074
- ↑ Cao W, Sohail M, Liu G, Koumbadinga GA, Lobo VG, Xie J. Differential effects of PKA-controlled CaMKK2 variants on neuronal differentiation. RNA Biol. 2011 Nov-Dec;8(6):1061-72. doi: 10.4161/rna.8.6.16691. Epub 2011 Nov 1. PMID:21957496 doi:http://dx.doi.org/10.4161/rna.8.6.16691
- ↑ Asquith CRM, Godoi PH, Counago RM, Laitinen T, Scott JW, Langendorf CG, Oakhill JS, Drewry DH, Zuercher WJ, Koutentis PA, Willson TM, Kalogirou AS. 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors. Molecules. 2018 May 19;23(5). pii: molecules23051221. doi:, 10.3390/molecules23051221. PMID:29783765 doi:http://dx.doi.org/10.3390/molecules23051221
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