4ekl - Revision history

OCA at 07:15, 28 September 2022

OCA — Wed, 28 Sep 2022 07:15:09 GMT

←Older revision		Revision as of 07:15, 28 September 2022
Line 1:		Line 1:

	==Akt1 with GDC0068==		==Akt1 with GDC0068==
-	<StructureSection load='4ekl' size='340' side='right' caption='[[4ekl]], [[Resolution\|resolution]] 2.00Å' scene=''>	+	<StructureSection load='4ekl' size='340' side='right'caption='[[4ekl]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ekl]] 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=4EKL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4EKL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ekl]] 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=4EKL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4EKL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RF:(2S)-2-(4-CHLOROPHENYL)-1-{4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-3-(PROPAN-2-YLAMINO)PROPAN-1-ONE'>0RF</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0RF:(2S)-2-(4-CHLOROPHENYL)-1-{4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-3-(PROPAN-2-YLAMINO)PROPAN-1-ONE'>0RF</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ekl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ekl OCA], [https://pdbe.org/4ekl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ekl RCSB], [https://www.ebi.ac.uk/pdbsum/4ekl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ekl ProSAT]</span></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ekk\|4ekk]]</td></tr>~~	+
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKT1, PKB, RAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4ekl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ekl OCA], [~~http~~://pdbe.org/4ekl PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ekl RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ekl PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ekl ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[~~http~~://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[~~http~~://omim.org/entry/114500 114500]]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[~~http~~://omim.org/entry/176920 176920]]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.<ref>PMID:18954143</ref> <ref>PMID:21793738</ref>	+	[[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[https://omim.org/entry/176920 176920]]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.<ref>PMID:18954143</ref> <ref>PMID:21793738</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref> AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref>	+	[[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref> AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4ekl" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ekl" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific serine/threonine protein kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Brandhuber~~, B J~~]]	+	[[Category: Brandhuber BJ]]
-	[[Category: Morales~~, T H~~]]	+	[[Category: Morales TH]]
-	[[Category: Vigers~~, G P.A~~]]	+	[[Category: Vigers GPA]]
-	[[Category: Wu, W I]]	+	[[Category: Wu W-I]]
-	~~[[Category: Phosphotransferase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 19:53, 24 January 2018

OCA — Wed, 24 Jan 2018 19:53:48 GMT

←Older revision		Revision as of 19:53, 24 January 2018
Line 24:		Line 24:
	</div>		</div>
	<div class="pdbe-citations 4ekl" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ekl" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:04, 4 August 2016

OCA — Thu, 04 Aug 2016 16:04:03 GMT

←Older revision		Revision as of 16:04, 4 August 2016
Line 1:		Line 1:
		+
	==Akt1 with GDC0068==		==Akt1 with GDC0068==
	<StructureSection load='4ekl' size='340' side='right' caption='[[4ekl]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='4ekl' size='340' side='right' caption='[[4ekl]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ekl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EKL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EKL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ekl]] 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=4EKL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EKL FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RF:(2S)-2-(4-CHLOROPHENYL)-1-{4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-3-(PROPAN-2-YLAMINO)PROPAN-1-ONE'>0RF</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RF:(2S)-2-(4-CHLOROPHENYL)-1-{4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-3-(PROPAN-2-YLAMINO)PROPAN-1-ONE'>0RF</scene></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='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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ekk\|4ekk]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ekk\|4ekk]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKT1, PKB, RAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKT1, PKB, RAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ekl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ekl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ekl RCSB], [http://www.ebi.ac.uk/pdbsum/4ekl PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ekl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ekl OCA], [http://pdbe.org/4ekl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ekl RCSB], [http://www.ebi.ac.uk/pdbsum/4ekl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ekl ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 22:		Line 23:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4ekl" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 29:		Line 31:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Brandhuber, B J]]		[[Category: Brandhuber, B J]]

OCA at 11:13, 21 December 2014

OCA — Sun, 21 Dec 2014 11:13:37 GMT

←Older revision		Revision as of 11:13, 21 December 2014
Line 1:		Line 1:
-	{~~{STRUCTURE_4ekl~~\| ~~PDB~~=4ekl \| ~~SCENE~~= }}	+	==Akt1 with GDC0068==
-	===~~Akt1 with GDC0068~~===	+	<StructureSection load='4ekl' size='340' side='right' caption='[[4ekl]], [[Resolution\|resolution]] 2.00Å' scene=''>
-	~~{{ABSTRACT_PUBMED_22569334}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ekl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EKL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EKL FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0RF:(2S)-2-(4-CHLOROPHENYL)-1-{4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZIN-1-YL}-3-(PROPAN-2-YLAMINO)PROPAN-1-ONE'>0RF</scene></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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ekk\|4ekk]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">AKT1, PKB, RAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ekl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ekl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ekl RCSB], [http://www.ebi.ac.uk/pdbsum/4ekl PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[http://omim.org/entry/176920 176920]]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.<ref>PMID:18954143</ref> <ref>PMID:21793738</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref> AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The protein serine-threonine kinase Akt undergoes a substantial conformational change upon activation, which is induced by the phosphorylation of two critical regulatory residues, threonine 308 and serine 473. Paradoxically, treating cells with adenosine 5'-triphosphate (ATP)-competitive inhibitors of Akt results in increased phosphorylation of both residues. We show that binding of ATP-competitive inhibitors stabilized a conformation in which both phosphorylated sites were inaccessible to phosphatases. ATP binding also produced this protection of the phosphorylated sites, whereas interaction with its hydrolysis product adenosine 5'-diphosphate (ADP) or allosteric Akt inhibitors resulted in increased accessibility of these phosphorylated residues. ATP-competitive inhibitors mimicked ATP by targeting active Akt. Forms of Akt activated by an oncogenic mutation or myristoylation were more potently inhibited by the ATP-competitive inhibitors than was wild-type Akt. These data support a new model of kinase regulation, wherein nucleotides modulate an on-off switch in Akt through conformational changes, which is disrupted by ATP-competitive inhibitors.

-	~~==Disease==~~	+	An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt.,Lin K, Lin J, Wu WI, Ballard J, Lee BB, Gloor SL, Vigers GP, Morales TH, Friedman LS, Skelton N, Brandhuber BJ Sci Signal. 2012 May 8;5(223):ra37. PMID:22569334<ref>PMID:22569334</ref>
-	~~[[http://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause~~ of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[http://omim.org/entry/176920 176920]]. ~~A highly variable~~, ~~severe disorder of asymmetric and disproportionate overgrowth of body parts~~, ~~connective tissue nevi~~, ~~epidermal nevi~~, ~~dysregulated adipose tissue~~, ~~and vascular malformations~~. ~~Many features of Proteus syndrome overlap with other overgrowth syndromes~~.~~<ref>~~PMID:~~18954143</ref>~~<ref>PMID:~~21793738~~</ref>	+

-	~~==Function==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[http:~~/~~/www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1~~, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a ~~range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible~~ of the ~~regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface~~. ~~Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling~~. ~~Phosphorylation~~ of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<~~ref~~>PMID:1718748</ref><ref>PMID:9829964</ref><ref>PMID:9512493</ref><ref>PMID:10358075</ref><ref>PMID:10576742</ref><ref>PMID:10926925</ref><ref>PMID:11154276</ref><ref>PMID:11994271</ref><ref>PMID:12042314</ref><ref>PMID:12150915</ref><ref>PMID:12244301</ref><ref>PMID:12878163</ref><ref>PMID:16139227</ref><ref>PMID:16417524</ref><ref>PMID:16982699</ref><ref>PMID:17726016</ref><ref>PMID:18507042</ref><ref>PMID:19592491</ref><ref>PMID:19934221</ref><ref>PMID:20086174</ref><ref>PMID:19940129</ref><ref>PMID:20682768</ref><ref>PMID:20471940</ref><ref>PMID:20231902</ref><ref>PMID:20333297</ref> AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref><ref>PMID:9829964</ref><ref>PMID:9512493</ref><ref>PMID:10358075</ref><ref>PMID:10576742</ref><ref>PMID:10926925</ref><ref>PMID:11154276</ref><ref>PMID:11994271</ref><ref>PMID:12042314</ref><ref>PMID:12150915</ref><ref>PMID:12244301</ref><ref>PMID:12878163</ref><ref>PMID:16139227</ref><ref>PMID:16417524</ref><ref>PMID:16982699</ref><ref>PMID:17726016</ref><ref>PMID:18507042</ref><ref>PMID:19592491</ref><ref>PMID:19934221</ref><ref>PMID:20086174</ref><ref>PMID:19940129</ref><ref>PMID:20682768</ref><ref>PMID:20471940</ref><ref>PMID:20231902</ref><ref>PMID:20333297</~~ref~~>	+	</div>

-	==~~About this Structure~~==	+	==See Also==
-	[[~~4ekl]] is a 1 chain structure with sequence from [http://en.wikipedia.org~~/~~wiki~~/~~Homo_sapiens Homo sapiens~~]~~. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EKL OCA~~].	+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:022569334</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Brandhuber, B J.]]	+	[[Category: Brandhuber, B J]]
-	[[Category: Morales, T H.]]	+	[[Category: Morales, T H]]
	[[Category: Vigers, G P.A]]		[[Category: Vigers, G P.A]]
-	[[Category: Wu, W I.]]	+	[[Category: Wu, W I]]
	[[Category: Phosphotransferase]]		[[Category: Phosphotransferase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 22:01, 24 March 2013

OCA — Sun, 24 Mar 2013 22:01:22 GMT

←Older revision		Revision as of 22:01, 24 March 2013
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-	[[Image:4ekl.jpg\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_4ekl", creates the "Structure Box" on the page.
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	{{STRUCTURE_4ekl\| PDB=4ekl \| SCENE= }}		{{STRUCTURE_4ekl\| PDB=4ekl \| SCENE= }}
-
	===Akt1 with GDC0068===		===Akt1 with GDC0068===
		+	{{ABSTRACT_PUBMED_22569334}}

		+	==Disease==
		+	[[http://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[http://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[http://omim.org/entry/114500 114500]]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[http://omim.org/entry/176920 176920]]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.<ref>PMID:18954143</ref><ref>PMID:21793738</ref>

-	<!--	+	==Function==
-	~~The line below~~ this ~~paragraph~~, ~~{{ABSTRACT_PUBMED_22569334}}~~, ~~adds~~ the ~~Publication Abstract~~ to the ~~page~~	+	[[http://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref><ref>PMID:9829964</ref><ref>PMID:9512493</ref><ref>PMID:10358075</ref><ref>PMID:10576742</ref><ref>PMID:10926925</ref><ref>PMID:11154276</ref><ref>PMID:11994271</ref><ref>PMID:12042314</ref><ref>PMID:12150915</ref><ref>PMID:12244301</ref><ref>PMID:12878163</ref><ref>PMID:16139227</ref><ref>PMID:16417524</ref><ref>PMID:16982699</ref><ref>PMID:17726016</ref><ref>PMID:18507042</ref><ref>PMID:19592491</ref><ref>PMID:19934221</ref><ref>PMID:20086174</ref><ref>PMID:19940129</ref><ref>PMID:20682768</ref><ref>PMID:20471940</ref><ref>PMID:20231902</ref><ref>PMID:20333297</ref> AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref><ref>PMID:9829964</ref><ref>PMID:9512493</ref><ref>PMID:10358075</ref><ref>PMID:10576742</ref><ref>PMID:10926925</ref><ref>PMID:11154276</ref><ref>PMID:11994271</ref><ref>PMID:12042314</ref><ref>PMID:12150915</ref><ref>PMID:12244301</ref><ref>PMID:12878163</ref><ref>PMID:16139227</ref><ref>PMID:16417524</ref><ref>PMID:16982699</ref><ref>PMID:17726016</ref><ref>PMID:18507042</ref><ref>PMID:19592491</ref><ref>PMID:19934221</ref><ref>PMID:20086174</ref><ref>PMID:19940129</ref><ref>PMID:20682768</ref><ref>PMID:20471940</ref><ref>PMID:20231902</ref><ref>PMID:20333297</ref>
-	(as ~~it appears~~ on ~~PubMed~~ at ~~http~~:/~~/www~~.~~pubmed~~.~~gov~~), ~~where 22569334 is~~ the ~~PubMed ID number~~.	+
-	-->	+
-	~~{{ABSTRACT_PUBMED_22569334}}~~	+

	==About this Structure==		==About this Structure==
Line 22:		Line 13:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:022569334</ref><references group="xtra"/>	+	<ref group="xtra">PMID:022569334</ref><references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]

OCA at 06:05, 23 May 2012

OCA — Wed, 23 May 2012 06:05:51 GMT

←Older revision		Revision as of 06:05, 23 May 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:4ekl.jpg\|left\|200px]]

-	The ~~entry 4ekl~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_4ekl", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_4ekl\| PDB=4ekl \| SCENE= }}

-	~~Authors: Wu, W.-I., Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.~~	+	===Akt1 with GDC0068===

-	~~Description~~: ~~Akt1~~ with ~~GDC0068~~	+
		+	<!--
		+	The line below this paragraph, {{ABSTRACT_PUBMED_22569334}}, adds the Publication Abstract to the page
		+	(as it appears on PubMed at http://www.pubmed.gov), where 22569334 is the PubMed ID number.
		+	-->
		+	{{ABSTRACT_PUBMED_22569334}}
		+
		+	==About this Structure==
		+	[[4ekl]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EKL OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:022569334</ref><references group="xtra"/>
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Brandhuber, B J.]]
		+	[[Category: Morales, T H.]]
		+	[[Category: Vigers, G P.A]]
		+	[[Category: Wu, W I.]]
		+	[[Category: Phosphotransferase]]
		+	[[Category: Transferase]]

OCA at 08:48, 16 May 2012

OCA — Wed, 16 May 2012 08:48:16 GMT

←Older revision		Revision as of 08:48, 16 May 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4ekl is ON HOLD	+	The entry 4ekl is ON HOLD until Paper Publication

	Authors: Wu, W.-I., Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.		Authors: Wu, W.-I., Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.

	Description: Akt1 with GDC0068		Description: Akt1 with GDC0068

OCA at 08:47, 9 May 2012

OCA — Wed, 09 May 2012 08:47:32 GMT

←Older revision		Revision as of 08:47, 9 May 2012
Line 3:		Line 3:
	The entry 4ekl is ON HOLD		The entry 4ekl is ON HOLD

-	Authors: Wu, ~~Wen~~-I, Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.	+	Authors: Wu, W.-I., Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.

	Description: Akt1 with GDC0068		Description: Akt1 with GDC0068

OCA: Protected "4ekl" [edit=sysop:move=sysop]

OCA — Wed, 18 Apr 2012 07:33:49 GMT

Protected "4ekl" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:33, 18 April 2012

OCA: New page: '''Unreleased structure''' The entry 4ekl is ON HOLD Authors: Wu, Wen-I, Vigers, G.P.A, Morales, T.H., Brandhuber, B.J. Description: Akt1 with GDC0068

OCA — Wed, 18 Apr 2012 07:33:48 GMT

New page: '''Unreleased structure''' The entry 4ekl is ON HOLD Authors: Wu, Wen-I, Vigers, G.P.A, Morales, T.H., Brandhuber, B.J. Description: Akt1 with GDC0068

New page

'''Unreleased structure'''

The entry 4ekl is ON HOLD

Authors: Wu, Wen-I, Vigers, G.P.A, Morales, T.H., Brandhuber, B.J.

Description: Akt1 with GDC0068