View source for 8tuc


==Unphosphorylated CaMKK2 in complex with CC-8977==
<StructureSection load='8tuc' size='340' side='right'caption='[[8tuc]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tuc]] 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=8TUC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TUC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</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=O7I:(4M)-2-cyclopentyl-4-(7-ethoxyquinazolin-4-yl)benzoic+acid'>O7I</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=8tuc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tuc OCA], [https://pdbe.org/8tuc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tuc RCSB], [https://www.ebi.ac.uk/pdbsum/8tuc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tuc ProSAT]</span></td></tr>
</table>
== 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 ==
CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated in tumors including hepatocellular carcinoma, prostate, breast, and gastric cancer, and genetic deletion in myeloid cells results in increased antitumor immunity in several syngeneic models. Validation of the biological roles of CaMKK2 has relied on genetic deletion or small molecule inhibitors with activity against several biological targets. We sought to generate selective inhibitors and degraders to understand the biological impact of inhibiting catalytic activity and scaffolding and the potential therapeutic benefits of targeting CaMKK2. We report herein selective, ligand-efficient inhibitors and ligand-directed degraders of CaMKK2 that were used to probe immune and tumor intrinsic biology. These molecules provide two distinct strategies for ablating CaMKK2 signaling in vitro and in vivo.

Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).,Chen Y, Whitefield B, Nevius E, Hill M, DelRosario J, Sinitsyna N, Shanmugasundaram V, Mukherjee D, Shi L, Mayne CG, Rousseau AM, Bernard SM, Buenviaje J, Khambatta G, El Samin M, Wallace M, Nie Z, Sivakumar P, Hamann LG, McDonnell DP, D'Agostino LA J Med Chem. 2023 Dec 14;66(23):15750-15760. doi: 10.1021/acs.jmedchem.3c01137. , Epub 2023 Nov 27. PMID:38009718<ref>PMID:38009718</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8tuc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bernard SM]]
[[Category: D'Agostino L]]
[[Category: Shanmugasundaram V]]