2uw9: Difference between revisions

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<StructureSection load='2uw9' size='340' side='right'caption='[[2uw9]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='2uw9' size='340' side='right'caption='[[2uw9]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2uw9]] is a 2 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=2UW9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2UW9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[2uw9]] is a 2 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=2UW9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2UW9 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GVP:4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE'>GVP</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]] 2.1&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GVP:4-(4-CHLOROPHENYL)-4-[4-(1H-PYRAZOL-4-YL)PHENYL]PIPERIDINE'>GVP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1gng|1gng]], [[1h8f|1h8f]], [[1i09|1i09]], [[1j1b|1j1b]], [[1j1c|1j1c]], [[1o6k|1o6k]], [[1o6l|1o6l]], [[1o9u|1o9u]], [[1pyx|1pyx]], [[1q3d|1q3d]], [[1q3w|1q3w]], [[1q41|1q41]], [[1q4l|1q4l]], [[1q5k|1q5k]], [[1r0e|1r0e]], [[1uv5|1uv5]], [[1gzk|1gzk]], [[1gzn|1gzn]], [[1gzo|1gzo]], [[1mrv|1mrv]], [[1mry|1mry]], [[1p6s|1p6s]], [[2jdo|2jdo]], [[2jdr|2jdr]]</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=2uw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uw9 OCA], [https://pdbe.org/2uw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2uw9 RCSB], [https://www.ebi.ac.uk/pdbsum/2uw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2uw9 ProSAT]</span></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=2uw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uw9 OCA], [http://pdbe.org/2uw9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2uw9 RCSB], [http://www.ebi.ac.uk/pdbsum/2uw9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2uw9 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/GSK3B_HUMAN GSK3B_HUMAN]] Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation.<ref>PMID:1846781</ref> <ref>PMID:8397507</ref> <ref>PMID:9072970</ref> <ref>PMID:9819408</ref> <ref>PMID:11430833</ref> <ref>PMID:14690523</ref> <ref>PMID:15448698</ref> <ref>PMID:18348280</ref> <ref>PMID:20932480</ref> <ref>PMID:20937854</ref> <ref>PMID:22514281</ref> <ref>PMID:12554650</ref> 
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/uw/2uw9_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/uw/2uw9_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </jmolCheckbox>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Barford D]]
[[Category: Barford, D]]
[[Category: Berdini V]]
[[Category: Berdini, V]]
[[Category: Boyle RG]]
[[Category: Boyle, R G]]
[[Category: Carr RA]]
[[Category: Carr, R A]]
[[Category: Davies TG]]
[[Category: Davies, T G]]
[[Category: Downham R]]
[[Category: Downham, R]]
[[Category: Garrett MD]]
[[Category: Garrett, M D]]
[[Category: Saxty G]]
[[Category: Saxty, G]]
[[Category: Verdonk ML]]
[[Category: Verdonk, M L]]
[[Category: Woodhead SJ]]
[[Category: Woodhead, S J]]
[[Category: Wyatt PG]]
[[Category: Wyatt, P G]]
[[Category: Alternative splicing]]
[[Category: Atp-binding]]
[[Category: Kinase]]
[[Category: Nucleotide-binding]]
[[Category: Phosphorylation]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Transferase]]
[[Category: Transferase-inhibitor complex]]
[[Category: Transferase/inhibitor]]
[[Category: Wnt signaling pathway]]

Latest revision as of 04:25, 21 November 2024

STRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH 4-(4-chloro-phenyl)-4-(4-(1H-pyrazol-4-yl)-phenyl)-piperidineSTRUCTURE OF PKB-BETA (AKT2) COMPLEXED WITH 4-(4-chloro-phenyl)-4-(4-(1H-pyrazol-4-yl)-phenyl)-piperidine

Structural highlights

2uw9 is a 2 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 2.1Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Using fragment-based screening techniques, 5-methyl-4-phenyl-1H-pyrazole (IC50 80 microM) was identified as a novel, low molecular weight inhibitor of protein kinase B (PKB). Herein we describe the rapid elaboration of highly potent and ligand efficient analogues using a fragment growing approach. Iterative structure-based design was supported by protein-ligand structure determinations using a PKA-PKB "chimera" and a final protein-ligand structure of a lead compound in PKBbeta itself.

Identification of inhibitors of protein kinase B using fragment-based lead discovery.,Saxty G, Woodhead SJ, Berdini V, Davies TG, Verdonk ML, Wyatt PG, Boyle RG, Barford D, Downham R, Garrett MD, Carr RA J Med Chem. 2007 May 17;50(10):2293-6. Epub 2007 Apr 24. PMID:17451234[1]

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

See Also

References

  1. ↑ Saxty G, Woodhead SJ, Berdini V, Davies TG, Verdonk ML, Wyatt PG, Boyle RG, Barford D, Downham R, Garrett MD, Carr RA. Identification of inhibitors of protein kinase B using fragment-based lead discovery. J Med Chem. 2007 May 17;50(10):2293-6. Epub 2007 Apr 24. PMID:17451234 doi:10.1021/jm070091b

2uw9, resolution 2.10Å

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