6buu - Revision history

OCA at 14:50, 4 October 2023

2023-10-04T14:50:40Z

←Older revision		Revision as of 14:50, 4 October 2023
Line 3:		Line 3:
	<StructureSection load='6buu' size='340' side='right'caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='6buu' size='340' side='right'caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6buu]] is a 4 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=6BUU OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6BUU FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6buu]] is a 4 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=6BUU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BUU FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name~~=~~'pdbligand=MN:MANGANESE+(II)+ION'>MN</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]] 2.4Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=~~SEP~~:~~PHOSPHOSERINE~~'>~~SEP~~</scene>, <scene name='pdbligand=~~TPO~~:~~PHOSPHOTHREONINE~~'>~~TPO~~</scene>, <scene name='pdbligand=~~ZXW~~:'>~~ZXW~~</scene><~~/td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=ZXW:5-O-[(S)-{[(R)-{[(R)-[(2-{[(2S)-2-amino-3-oxopropyl]amino}-2-oxoethyl)sulfanyl](hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]adenosine'>ZXW</scene></td></tr>
-	~~<tr id~~='~~related'><td class~~=~~"sblockLbl"><b>[[Related_structure\|Related~~:~~]]</b~~></td><~~td class="sblockDat">[[6c01\|6c01]]</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=6buu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6buu OCA], [https://pdbe.org/6buu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6buu RCSB], [https://www.ebi.ac.uk/pdbsum/6buu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6buu ProSAT]</span></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=6buu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6buu OCA], [~~http~~://pdbe.org/6buu PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6buu RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6buu PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6buu 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 26:		Line 23:

	==See Also==		==See Also==
-	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]	+	*[[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: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Chu N]]
-	[[Category: Chu, N]]	+	[[Category: Cole PA]]
-	[[Category: Cole~~, P A~~]]	+	[[Category: Gabelli SB]]
-	[[Category: Gabelli~~, S B]]~~	+
-	~~[[Category: Akt1]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Phosphorylated tail]]~~	+
-	~~[[Category: Rac-alpha serine/theronine-protein kinase]]~~	+
-	~~[[Category: Semi-synthesis]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 09:55, 4 December 2019

2019-12-04T09:55:33Z

←Older revision		Revision as of 09:55, 4 December 2019
Line 1:		Line 1:

	==Crystal structure of AKT1 (aa 144-480) with a bisubstrate==		==Crystal structure of AKT1 (aa 144-480) with a bisubstrate==
-	<StructureSection load='6buu' size='340' side='right' caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='6buu' size='340' side='right'caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6buu]] is a 4 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=6BUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUU FirstGlance]. <br>		<table><tr><td colspan='2'>[[6buu]] is a 4 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=6BUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUU FirstGlance]. <br>
Line 24:		Line 24:
	</div>		</div>
	<div class="pdbe-citations 6buu" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6buu" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Serine/threonine protein kinase\|Serine/threonine protein kinase]]
	== References ==		== References ==
	<references/>		<references/>
Line 29:		Line 32:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Chu, N]]		[[Category: Chu, N]]

OCA at 10:25, 5 September 2018

2018-09-05T10:25:33Z

←Older revision		Revision as of 10:25, 5 September 2018
Line 3:		Line 3:
	<StructureSection load='6buu' size='340' side='right' caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='6buu' size='340' side='right' caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6buu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUU FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6buu]] is a 4 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=6BUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUU FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=ZXW:'>ZXW</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=ZXW:'>ZXW</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6c01\|6c01]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6c01\|6c01]]</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=6buu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6buu OCA], [http://pdbe.org/6buu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6buu RCSB], [http://www.ebi.ac.uk/pdbsum/6buu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6buu ProSAT]</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=6buu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6buu OCA], [http://pdbe.org/6buu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6buu RCSB], [http://www.ebi.ac.uk/pdbsum/6buu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6buu ProSAT]</span></td></tr>
Line 27:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Chu, N]]		[[Category: Chu, N]]

OCA at 06:04, 22 August 2018

2018-08-22T06:04:40Z

←Older revision		Revision as of 06:04, 22 August 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6buu is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of AKT1 (aa 144-480) with a bisubstrate==
		+	<StructureSection load='6buu' size='340' side='right' caption='[[6buu]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6buu]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BUU FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=ZXW:'>ZXW</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6c01\|6c01]]</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=6buu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6buu OCA], [http://pdbe.org/6buu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6buu RCSB], [http://www.ebi.ac.uk/pdbsum/6buu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6buu ProSAT]</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 ==
		+	Akt is a critical protein kinase that drives cancer proliferation, modulates metabolism, and is activated by C-terminal phosphorylation. The current structural model for Akt activation by C-terminal phosphorylation has centered on intramolecular interactions between the C-terminal tail and the N lobe of the kinase domain. Here, we employ expressed protein ligation to produce site-specifically phosphorylated forms of purified Akt1 that are well suited for mechanistic analysis. Using biochemical, crystallographic, and cellular approaches, we determine that pSer473-Akt activation is driven by an intramolecular interaction between the C-tail and the pleckstrin homology (PH)-kinase domain linker that relieves PH domain-mediated Akt1 autoinhibition. Moreover, dual phosphorylation at Ser477/Thr479 activates Akt1 through a different allosteric mechanism via an apparent activation loop interaction that reduces autoinhibition by the PH domain and weakens PIP3 affinity. These results provide a new framework for understanding how Akt is controlled in cell signaling and suggest distinct functions for differentially modified Akt forms.

-	~~Authors~~:	+	Akt Kinase Activation Mechanisms Revealed Using Protein Semisynthesis.,Chu N, Salguero AL, Liu AZ, Chen Z, Dempsey DR, Ficarro SB, Alexander WM, Marto JA, Li Y, Amzel LM, Gabelli SB, Cole PA Cell. 2018 Aug 9;174(4):897-907.e14. doi: 10.1016/j.cell.2018.07.003. Epub 2018, Aug 2. PMID:30078705<ref>PMID:30078705</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 6buu" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Chu, N]]
		+	[[Category: Cole, P A]]
		+	[[Category: Gabelli, S B]]
		+	[[Category: Akt1]]
		+	[[Category: Kinase]]
		+	[[Category: Phosphorylated tail]]
		+	[[Category: Rac-alpha serine/theronine-protein kinase]]
		+	[[Category: Semi-synthesis]]
		+	[[Category: Transferase]]

OCA at 19:45, 9 August 2018

2018-08-09T19:45:32Z

←Older revision		Revision as of 19:45, 9 August 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6buu is ON HOLD until ~~sometime in the future~~	+	The entry 6buu is ON HOLD until Paper Publication

	Authors:		Authors:

OCA at 03:58, 30 May 2018

2018-05-30T03:58:16Z

←Older revision		Revision as of 03:58, 30 May 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6buu is ON HOLD	+	The entry 6buu is ON HOLD until sometime in the future

	Authors:		Authors:

OCA at 04:43, 31 January 2018

2018-01-31T04:43:57Z

←Older revision		Revision as of 04:43, 31 January 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6buu is ON HOLD ~~until sometime in the future~~	+	The entry 6buu is ON HOLD

	Authors:		Authors:

OCA at 07:18, 27 December 2017

2017-12-27T07:18:29Z

←Older revision		Revision as of 07:18, 27 December 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6buu is ON HOLD	+	The entry 6buu is ON HOLD until sometime in the future

	Authors:		Authors:

OCA: Protected "6buu" [edit=sysop:move=sysop]

2017-12-20T05:02:30Z

Protected "6buu" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:02, 20 December 2017

OCA: New page: '''Unreleased structure''' The entry 6buu is ON HOLD Authors: Description: Category: Unreleased Structures

2017-12-20T05:02:28Z

New page: '''Unreleased structure''' The entry 6buu is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6buu is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]