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6t28

From Proteopedia

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Current revision

Crystal structure of human calmodulin-dependent protein kinase 1D (CAMK1D) bound to compound 19 (CS640)

Structural highlights

6t28 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 1.55Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KCC1D_HUMAN Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model.,Fromont C, Atzori A, Kaur D, Hashmi L, Greco G, Cabanillas A, Nguyen HV, Jones DH, Garzon M, Varela A, Stevenson B, Iacobini GP, Lenoir M, Rajesh S, Box C, Kumar J, Grant P, Novitskaya V, Morgan J, Sorrell FJ, Redondo C, Kramer A, Harris CJ, Leighton B, Vickers SP, Cheetham SC, Kenyon C, Grabowska AM, Overduin M, Berditchevski F, Weston CJ, Knapp S, Fischer PM, Butterworth S J Med Chem. 2020 Jun 22. doi: 10.1021/acs.jmedchem.9b01803. PMID:32433887^[5]

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

References

↑ Verploegen S, Lammers JW, Koenderman L, Coffer PJ. Identification and characterization of CKLiK, a novel granulocyte Ca(++)/calmodulin-dependent kinase. Blood. 2000 Nov 1;96(9):3215-23. PMID:11050006
↑ Verploegen S, Ulfman L, van Deutekom HW, van Aalst C, Honing H, Lammers JW, Koenderman L, Coffer PJ. Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function. Blood. 2005 Aug 1;106(3):1076-83. Epub 2005 Apr 19. PMID:15840691 doi:http://dx.doi.org/10.1182/blood-2004-09-3755
↑ Sakagami H, Kamata A, Nishimura H, Kasahara J, Owada Y, Takeuchi Y, Watanabe M, Fukunaga K, Kondo H. Prominent expression and activity-dependent nuclear translocation of Ca2+/calmodulin-dependent protein kinase Idelta in hippocampal neurons. Eur J Neurosci. 2005 Dec;22(11):2697-707. PMID:16324104 doi:http://dx.doi.org/10.1111/j.1460-9568.2005.04463.x
↑ Kamata A, Sakagami H, Tokumitsu H, Owada Y, Fukunaga K, Kondo H. Spatiotemporal expression of four isoforms of Ca2+/calmodulin-dependent protein kinase I in brain and its possible roles in hippocampal dendritic growth. Neurosci Res. 2007 Jan;57(1):86-97. Epub 2006 Oct 23. PMID:17056143 doi:http://dx.doi.org/10.1016/j.neures.2006.09.013
↑ Fromont C, Atzori A, Kaur D, Hashmi L, Greco G, Cabanillas A, Nguyen HV, Jones DH, Garzon M, Varela A, Stevenson B, Iacobini GP, Lenoir M, Rajesh S, Box C, Kumar J, Grant P, Novitskaya V, Morgan J, Sorrell FJ, Redondo C, Kramer A, Harris CJ, Leighton B, Vickers SP, Cheetham SC, Kenyon C, Grabowska AM, Overduin M, Berditchevski F, Weston CJ, Knapp S, Fischer PM, Butterworth S. Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model. J Med Chem. 2020 Jun 22. doi: 10.1021/acs.jmedchem.9b01803. PMID:32433887 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01803

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/6t28"

@@ Line 3: / Line 3: @@
 <StructureSection load='6t28' size='340' side='right'caption='[[6t28]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6t28]] 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=6T28 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6T28 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6t28]] 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=6T28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T28 FirstGlance]. <br>
-</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=M92:2-[(3~{S})-3-azanylpiperidin-1-yl]-4-[[2,6-di(propan-2-yl)pyridin-4-yl]amino]pyrimidine-5-carboxamide'>M92</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.55&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CAMK1D, CAMKID ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=M92:2-[(3~{S})-3-azanylpiperidin-1-yl]-4-[[2,6-di(propan-2-yl)pyridin-4-yl]amino]pyrimidine-5-carboxamide'>M92</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </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=6t28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t28 OCA], [https://pdbe.org/6t28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t28 RCSB], [https://www.ebi.ac.uk/pdbsum/6t28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t28 ProSAT]</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=6t28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t28 OCA], [http://pdbe.org/6t28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t28 RCSB], [http://www.ebi.ac.uk/pdbsum/6t28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t28 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KCC1D_HUMAN KCC1D_HUMAN]] Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.<ref>PMID:11050006</ref> <ref>PMID:15840691</ref> <ref>PMID:16324104</ref> <ref>PMID:17056143</ref>
+[https://www.uniprot.org/uniprot/KCC1D_HUMAN KCC1D_HUMAN] Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, activates CREB-dependent gene transcription, regulates calcium-mediated granulocyte function and respiratory burst and promotes basal dendritic growth of hippocampal neurons. In neutrophil cells, required for cytokine-induced proliferative responses and activation of the respiratory burst. Activates the transcription factor CREB1 in hippocampal neuron nuclei. May play a role in apoptosis of erythroleukemia cells. In vitro, phosphorylates transcription factor CREM isoform Beta.<ref>PMID:11050006</ref> <ref>PMID:15840691</ref> <ref>PMID:16324104</ref> <ref>PMID:17056143</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6t28" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Calcium/calmodulin dependent protein kinase 3D structures|Calcium/calmodulin dependent protein kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Calcium/calmodulin-dependent protein kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Butterworth, S]]
+[[Category: Butterworth S]]
-[[Category: Edwards, A M]]
+[[Category: Edwards AM]]
-[[Category: Knapp, S]]
+[[Category: Knapp S]]
-[[Category: Kraemer, A]]
+[[Category: Kraemer A]]
-[[Category: Structural genomic]]
+[[Category: Sorrell F]]
-[[Category: Sorrell, F]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Kinase]]
-[[Category: Sgc]]
-[[Category: Transferase]]

6t28

From Proteopedia

Current revision

Crystal structure of human calmodulin-dependent protein kinase 1D (CAMK1D) bound to compound 19 (CS640)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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