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| | ==Crystal structure of ULK2 in complexed with MRT68921== | | ==Crystal structure of ULK2 in complexed with MRT68921== |
| - | <StructureSection load='6qav' size='340' side='right' caption='[[6qav]], [[Resolution|resolution]] 2.05Å' scene=''> | + | <StructureSection load='6qav' size='340' side='right'caption='[[6qav]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6qav]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QAV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6qav]] 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=6QAV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QAV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HVH:~{N}-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1~{H}-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide'>HVH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.05Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HVH:~{N}-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1~{H}-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide'>HVH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=6qav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qav OCA], [http://pdbe.org/6qav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qav RCSB], [http://www.ebi.ac.uk/pdbsum/6qav PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qav ProSAT]</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=6qav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qav OCA], [https://pdbe.org/6qav PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qav RCSB], [https://www.ebi.ac.uk/pdbsum/6qav PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qav ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ULK2_HUMAN ULK2_HUMAN]] Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.<ref>PMID:18936157</ref> <ref>PMID:21460634</ref> <ref>PMID:21460635</ref> <ref>PMID:21690395</ref> <ref>PMID:21795849</ref> | + | [https://www.uniprot.org/uniprot/ULK2_HUMAN ULK2_HUMAN] Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.<ref>PMID:18936157</ref> <ref>PMID:21460634</ref> <ref>PMID:21460635</ref> <ref>PMID:21690395</ref> <ref>PMID:21795849</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6qav" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6qav" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Large Structures]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Chaikuad, A]] | + | [[Category: Bountra C]] |
| | + | [[Category: Chaikuad A]] |
| | + | [[Category: Edwards AM]] |
| | + | [[Category: Knapp S]] |
| | [[Category: Structural genomic]] | | [[Category: Structural genomic]] |
| - | [[Category: Edwards, A M]] | |
| - | [[Category: Knapp, S]] | |
| - | [[Category: Autophagy]] | |
| - | [[Category: Inhibitor complex]] | |
| - | [[Category: Kinase]] | |
| - | [[Category: Sgc]] | |
| - | [[Category: Transferase]] | |
| - | [[Category: Ulk2]] | |
| Structural highlights
Function
ULK2_HUMAN Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2. Here we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provides structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.
Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2).,Chaikuad A, Koschade SE, Stolz A, Zivkovic K, Pohl C, Shaid S, Ren H, Lambert LJ, Cosford NDP, Brandts CH, Knapp S Biochem J. 2019 Feb 19. pii: BCJ20190038. doi: 10.1042/BCJ20190038. PMID:30782972[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol. 2009 Jan;29(1):157-71. doi: 10.1128/MCB.01082-08. Epub 2008 Oct, 20. PMID:18936157 doi:http://dx.doi.org/10.1128/MCB.01082-08
- ↑ Loffler AS, Alers S, Dieterle AM, Keppeler H, Franz-Wachtel M, Kundu M, Campbell DG, Wesselborg S, Alessi DR, Stork B. Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop. Autophagy. 2011 Jul;7(7):696-706. Epub 2011 Jul 1. PMID:21460634
- ↑ Lee EJ, Tournier C. The requirement of uncoordinated 51-like kinase 1 (ULK1) and ULK2 in the regulation of autophagy. Autophagy. 2011 Jul;7(7):689-95. Epub 2011 Jul 1. PMID:21460635
- ↑ Cheong H, Lindsten T, Wu J, Lu C, Thompson CB. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11121-6. doi:, 10.1073/pnas.1107969108. Epub 2011 Jun 20. PMID:21690395 doi:http://dx.doi.org/10.1073/pnas.1107969108
- ↑ Jung CH, Seo M, Otto NM, Kim DH. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy. 2011 Oct;7(10):1212-21. doi: 10.4161/auto.7.10.16660. Epub 2011 Oct 1. PMID:21795849 doi:http://dx.doi.org/10.4161/auto.7.10.16660
- ↑ Chaikuad A, Koschade SE, Stolz A, Zivkovic K, Pohl C, Shaid S, Ren H, Lambert LJ, Cosford NDP, Brandts CH, Knapp S. Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2). Biochem J. 2019 Feb 19. pii: BCJ20190038. doi: 10.1042/BCJ20190038. PMID:30782972 doi:http://dx.doi.org/10.1042/BCJ20190038
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