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5vt1

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Revision as of 06:30, 17 April 2019

Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor

Structural highlights

5vt1 is a 1 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:	CAMKK2, CAMKKB, KIAA0787 (HUMAN)
Activity:	Calcium/calmodulin-dependent protein kinase, with EC number 2.7.11.17
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

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.,Asquith CRM, Godoi PH, Counago RM, Laitinen T, Scott JW, Langendorf CG, Oakhill JS, Drewry DH, Zuercher WJ, Koutentis PA, Willson TM, Kalogirou AS Molecules. 2018 May 19;23(5). pii: molecules23051221. doi:, 10.3390/molecules23051221. PMID:29783765^[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
↑ Asquith CRM, Godoi PH, Counago RM, Laitinen T, Scott JW, Langendorf CG, Oakhill JS, Drewry DH, Zuercher WJ, Koutentis PA, Willson TM, Kalogirou AS. 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors. Molecules. 2018 May 19;23(5). pii: molecules23051221. doi:, 10.3390/molecules23051221. PMID:29783765 doi:http://dx.doi.org/10.3390/molecules23051221

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/5vt1"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor==
-<StructureSection load='5vt1' size='340' side='right' caption='[[5vt1]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='5vt1' size='340' side='right'caption='[[5vt1]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5vt1]] 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=5VT1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VT1 FirstGlance]. <br>
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 5vt1" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Calcium/calmodulin-dependent protein kinase kinase|Calcium/calmodulin-dependent protein kinase kinase]]
 == References ==
 <references/>
@@ Line 26: / Line 29: @@
 [[Category: Calcium/calmodulin-dependent protein kinase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Arruda, P]]
 [[Category: Asquith, C R.M]]

5vt1

From Proteopedia

Revision as of 06:30, 17 April 2019

Crystal Structure of the Human CAMKK2B bound to a thiadiazinone benzamide inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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