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| ==Structure of death-associated protein Kinase 1 (dapk1) in complex with a ruthenium octasporine ligand (OSV)== | | ==Structure of death-associated protein Kinase 1 (dapk1) in complex with a ruthenium octasporine ligand (OSV)== |
| <StructureSection load='2yak' size='340' side='right' caption='[[2yak]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='2yak' size='340' side='right'caption='[[2yak]], [[Resolution|resolution]] 2.20Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[2yak]] 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=2YAK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YAK FirstGlance]. <br> | | <table><tr><td colspan='2'>[[2yak]] 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=2YAK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2YAK FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OSV:RUTHENIUM+OCTASPORINE+4'>OSV</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]] 2.2Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jkk|1jkk]], [[1p4f|1p4f]], [[2y0a|2y0a]], [[2w4j|2w4j]], [[2x0g|2x0g]], [[2y4v|2y4v]], [[2w4k|2w4k]], [[1jkt|1jkt]], [[1ig1|1ig1]], [[2xuu|2xuu]], [[1jkl|1jkl]], [[1jks|1jks]], [[2xzs|2xzs]], [[2y4p|2y4p]]</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OSV:RUTHENIUM+OCTASPORINE+4'>OSV</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=2yak FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yak OCA], [https://pdbe.org/2yak PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2yak RCSB], [https://www.ebi.ac.uk/pdbsum/2yak PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2yak 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=2yak FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yak OCA], [http://pdbe.org/2yak PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2yak RCSB], [http://www.ebi.ac.uk/pdbsum/2yak PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2yak ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/DAPK1_HUMAN DAPK1_HUMAN]] Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition.<ref>PMID:7828849</ref> <ref>PMID:10629061</ref> <ref>PMID:11579085</ref> <ref>PMID:11980920</ref> <ref>PMID:12730201</ref> <ref>PMID:15367680</ref> <ref>PMID:17703233</ref> <ref>PMID:17895359</ref> <ref>PMID:18422656</ref> <ref>PMID:18195017</ref> <ref>PMID:18995835</ref> <ref>PMID:19180116</ref> <ref>PMID:18974095</ref> <ref>PMID:21497122</ref> <ref>PMID:21408167</ref> Isoform 2 cannot induce apoptosis but can induce membrane blebbing.<ref>PMID:7828849</ref> <ref>PMID:10629061</ref> <ref>PMID:11579085</ref> <ref>PMID:11980920</ref> <ref>PMID:12730201</ref> <ref>PMID:15367680</ref> <ref>PMID:17703233</ref> <ref>PMID:17895359</ref> <ref>PMID:18422656</ref> <ref>PMID:18195017</ref> <ref>PMID:18995835</ref> <ref>PMID:19180116</ref> <ref>PMID:18974095</ref> <ref>PMID:21497122</ref> <ref>PMID:21408167</ref> | | [https://www.uniprot.org/uniprot/DAPK1_HUMAN DAPK1_HUMAN] Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition.<ref>PMID:7828849</ref> <ref>PMID:10629061</ref> <ref>PMID:11579085</ref> <ref>PMID:11980920</ref> <ref>PMID:12730201</ref> <ref>PMID:15367680</ref> <ref>PMID:17703233</ref> <ref>PMID:17895359</ref> <ref>PMID:18422656</ref> <ref>PMID:18195017</ref> <ref>PMID:18995835</ref> <ref>PMID:19180116</ref> <ref>PMID:18974095</ref> <ref>PMID:21497122</ref> <ref>PMID:21408167</ref> Isoform 2 cannot induce apoptosis but can induce membrane blebbing.<ref>PMID:7828849</ref> <ref>PMID:10629061</ref> <ref>PMID:11579085</ref> <ref>PMID:11980920</ref> <ref>PMID:12730201</ref> <ref>PMID:15367680</ref> <ref>PMID:17703233</ref> <ref>PMID:17895359</ref> <ref>PMID:18422656</ref> <ref>PMID:18195017</ref> <ref>PMID:18995835</ref> <ref>PMID:19180116</ref> <ref>PMID:18974095</ref> <ref>PMID:21497122</ref> <ref>PMID:21408167</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| The generation of synthetic compounds with exclusive target specificity is an extraordinary challenge of molecular recognition and demands novel design strategies, in particular for large and homologous protein families such as protein kinases with more than 500 members. Simple organic molecules often do not reach the necessary sophistication to fulfill this task. Here, we present six carefully tailored, stable metal-containing compounds in which unique and defined molecular geometries with natural-product-like structural complexity are constructed around octahedral ruthenium(II) or iridium(III) metal centers. Each of the six reported metal compounds displays high selectivity for an individual protein kinase, namely GSK3alpha, PAK1, PIM1, DAPK1, MLCK, and FLT4. Although being conventional ATP-competitive inhibitors, the combination of the unusual globular shape and rigidity characteristics, of these compounds facilitates the design of highly selective protein kinase inhibitors. Unique structural features of the octahedral coordination geometry allow novel interactions with the glycine-rich loop, which contribute significantly to binding potencies and selectivities. The sensitive correlation between metal coordination sphere and inhibition properties suggests that in this design, the metal is located at a "hot spot" within the ATP binding pocket, not too close to the hinge region where globular space is unavailable, and at the same time not too far out toward the solvent where the octahedral coordination sphere would not have a significant impact on potency and selectivity. This study thus demonstrates that inert (stable) octahedral metal complexes are sophisticated structural scaffolds for the design of highly selective chemical probes.
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| Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors.,Feng L, Geisselbrecht Y, Blanck S, Wilbuer A, Atilla-Gokcumen GE, Filippakopoulos P, Kraling K, Celik MA, Harms K, Maksimoska J, Marmorstein R, Frenking G, Knapp S, Essen LO, Meggers E J Am Chem Soc. 2011 Apr 20;133(15):5976-5986. Epub 2011 Mar 29. PMID:21446733<ref>PMID:21446733</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 2yak" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Death-associated protein kinase|Death-associated protein kinase]] | | *[[Death-associated protein kinase 3D structures|Death-associated protein kinase 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Human]] | | [[Category: Homo sapiens]] |
| [[Category: Non-specific serine/threonine protein kinase]] | | [[Category: Large Structures]] |
| [[Category: Atilla-Gokcumen, G E]] | | [[Category: Atilla-Gokcumen GE]] |
| [[Category: Blanck, S]] | | [[Category: Blanck S]] |
| [[Category: Celik, M A]] | | [[Category: Celik MA]] |
| [[Category: Essen, L O]] | | [[Category: Essen L-O]] |
| [[Category: Feng, L]] | | [[Category: Feng L]] |
| [[Category: Filippakopoulos, P]] | | [[Category: Filippakopoulos P]] |
| [[Category: Frenking, G]] | | [[Category: Frenking G]] |
| [[Category: Geisselbrecht, Y]] | | [[Category: Geisselbrecht Y]] |
| [[Category: Harms, K]] | | [[Category: Harms K]] |
| [[Category: Knapp, S]] | | [[Category: Knapp S]] |
| [[Category: Kraeling, K]] | | [[Category: Kraeling K]] |
| [[Category: Maksimoska, J]] | | [[Category: Maksimoska J]] |
| [[Category: Marmorstein, R]] | | [[Category: Marmorstein R]] |
| [[Category: Meggers, E]] | | [[Category: Meggers E]] |
| [[Category: Wilbuer, A]] | | [[Category: Wilbuer A]] |
| [[Category: Kinase inhibitor]]
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| [[Category: Octahedral ruthenium inhibitory complex]]
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| [[Category: Transferase]]
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