8tuc

From Proteopedia

(Difference between revisions)

Revision as of 11:48, 13 December 2023

Unphosphorylated CaMKK2 in complex with CC-8977

Structural highlights

8tuc is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.5Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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 Nov 27. doi: 10.1021/acs.jmedchem.3c01137. PMID:38009718^[5]

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

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
↑ 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. Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2). J Med Chem. 2023 Nov 27. PMID:38009718 doi:10.1021/acs.jmedchem.3c01137

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8tuc"

Categories: Homo sapiens | Large Structures | Bernard SM | D'Agostino L | Shanmugasundaram V

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8tuc is ON HOLD  until Paper Publication
+==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.
-Authors: Bernard, S.M., Shanmugasundaram, V., D''Agostino, L.
+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 Nov 27. doi: 10.1021/acs.jmedchem.3c01137. PMID:38009718<ref>PMID:38009718</ref>
-Description: Unphosphorylated CaMKK2 in complex with CC-8977
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: D''Agostino, L]]
+<div class="pdbe-citations 8tuc" style="background-color:#fffaf0;"></div>
-[[Category: Bernard, S.M]]
+== References ==
-[[Category: Shanmugasundaram, V]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bernard SM]]
+[[Category: D'Agostino L]]
+[[Category: Shanmugasundaram V]]

8tuc

From Proteopedia

Revision as of 11:48, 13 December 2023

Unphosphorylated CaMKK2 in complex with CC-8977

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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