2x39: Difference between revisions

Latest revision as of 01:29, 21 November 2024

Structure of 4-Amino-N-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin- 4-yl)piperidine-4-carboxamide bound to PKB

Structural highlights

2x39 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 1.93Å
Ligands:	TPO, X39
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

Protein kinase B (PKB or Akt) is an important component of intracellular signaling pathways regulating growth and survival. Signaling through PKB is frequently deregulated in cancer, and inhibitors of PKB therefore have potential as antitumor agents. The optimization of lipophilic substitution within a series of 4-benzyl-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-amines provided ATP-competitive, nanomolar inhibitors with up to 150-fold selectivity for inhibition of PKB over the closely related kinase PKA. Although active in cellular assays, compounds containing 4-amino-4-benzylpiperidines underwent metabolism in vivo, leading to rapid clearance and low oral bioavailability. Variation of the linker group between the piperidine and the lipophilic substituent identified 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as potent and orally bioavailable inhibitors of PKB. Representative compounds modulated biomarkers of signaling through PKB in vivo and strongly inhibited the growth of human tumor xenografts in nude mice at well-tolerated doses.

Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt).,McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, Ruddle R, Henley A, de Haven Brandon A, Valenti M, Davies TG, Fazal L, Seavers L, Raynaud FI, Eccles SA, Aherne GW, Garrett MD, Collins I J Med Chem. 2010 Feb 12. PMID:20151677^[1]

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

References

↑ McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, Ruddle R, Henley A, de Haven Brandon A, Valenti M, Davies TG, Fazal L, Seavers L, Raynaud FI, Eccles SA, Aherne GW, Garrett MD, Collins I. Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt). J Med Chem. 2010 Feb 12. PMID:20151677 doi:10.1021/jm901788j

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, Ruddle R, Henley A, de Haven Brandon A, Valenti M, Davies TG, Fazal L, Seavers L, Raynaud FI, Eccles SA, Aherne GW, Garrett MD, Collins I. Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt). J Med Chem. 2010 Feb 12. PMID:20151677 doi:10.1021/jm901788j

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='2x39' size='340' side='right'caption='[[2x39]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2x39]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2X39 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X39 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2x39]] 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=2X39 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2X39 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=X39:4-AMINO-N-(4-CHLOROBENZYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE'>X39</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]] 1.93&#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=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=X39:4-AMINO-N-(4-CHLOROBENZYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE'>X39</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2uw9|2uw9]], [[1o6k|1o6k]], [[1gng|1gng]], [[1h8f|1h8f]], [[1q3w|1q3w]], [[1i09|1i09]], [[1o9u|1o9u]], [[2x37|2x37]], [[2jdr|2jdr]], [[1o6l|1o6l]], [[1j1b|1j1b]], [[1r0e|1r0e]], [[1q41|1q41]], [[1q3d|1q3d]], [[2jld|2jld]], [[1q5k|1q5k]], [[2jdo|2jdo]], [[1pyx|1pyx]], [[1q4l|1q4l]], [[1j1c|1j1c]], [[1uv5|1uv5]]</div></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2x39 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2x39 OCA], [https://pdbe.org/2x39 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2x39 RCSB], [https://www.ebi.ac.uk/pdbsum/2x39 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2x39 ProSAT]</span></td></tr>
 </table>
-== Function ==
-[[https://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 ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 17: / Line 13: @@
    <jmolCheckbox>
      <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/x3/2x39_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>
    </jmolCheckbox>
@@ Line 38: / Line 34: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Aherne GW]]
-[[Category: Aherne, G W]]
+[[Category: Brandon AD]]
-[[Category: Brandon, A D]]
+[[Category: Caldwell JJ]]
-[[Category: Caldwell, J J]]
+[[Category: Cheung KM]]
-[[Category: Cheung, K M]]
+[[Category: Collins I]]
-[[Category: Collins, I]]
+[[Category: Davies TG]]
-[[Category: Davies, T G]]
+[[Category: Eccles SA]]
-[[Category: Eccles, S A]]
+[[Category: Fazal L]]
-[[Category: Fazal, L]]
+[[Category: Garrett MD]]
-[[Category: Garrett, M D]]
+[[Category: Henley A]]
-[[Category: Henley, A]]
+[[Category: Hunter LJ]]
-[[Category: Hunter, L J]]
+[[Category: McHardy T]]
-[[Category: McHardy, T]]
+[[Category: Raynaud FI]]
-[[Category: Raynaud, F I]]
+[[Category: Rowlands M]]
-[[Category: Rowlands, M]]
+[[Category: Ruddle R]]
-[[Category: Ruddle, R]]
+[[Category: Seavers L]]
-[[Category: Seavers, L]]
+[[Category: Taylor K]]
-[[Category: Taylor, K]]
+[[Category: Valenti M]]
-[[Category: Valenti, M]]
-[[Category: Kinase]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphoprotein]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Transferase]]
-[[Category: Wnt signaling pathway]]

2x39: Difference between revisions

Latest revision as of 01:29, 21 November 2024

Structure of 4-Amino-N-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin- 4-yl)piperidine-4-carboxamide bound to PKB

Structural highlights

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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