6yid

From Proteopedia

(Difference between revisions)

Revision as of 06:02, 20 January 2021

Crystal structure of ULK2 in complex with SBI-0206965

Structural highlights

6yid is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	ULK2, KIAA0623 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-negative breast cancer (TNBC). We previously reported SBI-0206965, a small molecule inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2). One inhibitor, SBP-7455 (compound 26), displayed improved binding affinity for ULK1/2 compared with SBI-0206965, potently inhibited ULK1/2 enzymatic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice. SBP-7455 inhibited starvation-induced autophagic flux in TNBC cells that were dependent on autophagy for survival and displayed synergistic cytotoxicity with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib against TNBC cells. These data suggest that combining ULK1/2 and PARP inhibition may have clinical utility for the treatment of TNBC.

Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer.,Ren H, Bakas NA, Vamos M, Chaikuad A, Limpert AS, Wimer CD, Brun SN, Lambert LJ, Tautz L, Celeridad M, Sheffler DJ, Knapp S, Shaw RJ, Cosford NDP J Med Chem. 2020 Dec 10;63(23):14609-14625. doi: 10.1021/acs.jmedchem.0c00873., Epub 2020 Nov 17. PMID:33200929^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Ren H, Bakas NA, Vamos M, Chaikuad A, Limpert AS, Wimer CD, Brun SN, Lambert LJ, Tautz L, Celeridad M, Sheffler DJ, Knapp S, Shaw RJ, Cosford NDP. Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer. J Med Chem. 2020 Dec 10;63(23):14609-14625. doi: 10.1021/acs.jmedchem.0c00873., Epub 2020 Nov 17. PMID:33200929 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00873

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6yid"

@@ Line 1: / Line 1: @@
 ==Crystal structure of ULK2 in complex with SBI-0206965==
-<StructureSection load='6yid' size='340' side='right'caption='[[6yid]]' scene=''>
+<StructureSection load='6yid' size='340' side='right'caption='[[6yid]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YID OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YID FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6yid]] 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=6YID OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6YID FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6yid FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yid OCA], [http://pdbe.org/6yid PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yid RCSB], [http://www.ebi.ac.uk/pdbsum/6yid PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yid ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDJ:2-({5-bromo-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}oxy)-N-methylbenzene-1-carboximidic+acid'>EDJ</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ULK2, KIAA0623 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://proteopedia.org/fgij/fg.htm?mol=6yid FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yid OCA], [http://pdbe.org/6yid PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6yid RCSB], [http://www.ebi.ac.uk/pdbsum/6yid PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6yid ProSAT]</span></td></tr>
 </table>
+== 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-negative breast cancer (TNBC). We previously reported SBI-0206965, a small molecule inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2). One inhibitor, SBP-7455 (compound 26), displayed improved binding affinity for ULK1/2 compared with SBI-0206965, potently inhibited ULK1/2 enzymatic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice. SBP-7455 inhibited starvation-induced autophagic flux in TNBC cells that were dependent on autophagy for survival and displayed synergistic cytotoxicity with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib against TNBC cells. These data suggest that combining ULK1/2 and PARP inhibition may have clinical utility for the treatment of TNBC.
+Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer.,Ren H, Bakas NA, Vamos M, Chaikuad A, Limpert AS, Wimer CD, Brun SN, Lambert LJ, Tautz L, Celeridad M, Sheffler DJ, Knapp S, Shaw RJ, Cosford NDP J Med Chem. 2020 Dec 10;63(23):14609-14625. doi: 10.1021/acs.jmedchem.0c00873., Epub 2020 Nov 17. PMID:33200929<ref>PMID:33200929</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6yid" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Bakas NA]]
+[[Category: Non-specific serine/threonine protein kinase]]
-[[Category: Chaikuad A]]
+[[Category: Bakas, N A]]
-[[Category: Cosford NDP]]
+[[Category: Chaikuad, A]]
-[[Category: Knapp S]]
+[[Category: Cosford, N D.P]]
-[[Category: Lambert LJ]]
+[[Category: Knapp, S]]
-[[Category: Ren H]]
+[[Category: Lambert, L J]]
+[[Category: Ren, H]]
+[[Category: Structural genomic]]
+[[Category: Autophagy]]
+[[Category: Chemical probe]]
+[[Category: Kinase]]
+[[Category: Kinase inhibitor]]
+[[Category: Sgc]]
+[[Category: Transferase]]
+[[Category: Ulk2]]

6yid

From Proteopedia

Revision as of 06:02, 20 January 2021

Crystal structure of ULK2 in complex with SBI-0206965

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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