4d2r - Revision history

OCA at 11:17, 9 May 2024

2024-05-09T11:17:00Z

←Older revision		Revision as of 11:17, 9 May 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D2R FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D2R FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</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]] 2.1Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [https://pdbe.org/4d2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [https://www.ebi.ac.uk/pdbsum/4d2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2r ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [https://pdbe.org/4d2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [https://www.ebi.ac.uk/pdbsum/4d2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2r ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:[https://omim.org/entry/270450 270450]]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.<ref>PMID:14657428</ref> <ref>PMID:15928254</ref>	+	[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:[https://omim.org/entry/270450 270450]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.<ref>PMID:14657428</ref> <ref>PMID:15928254</ref>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref> When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref>	+	[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref> When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 07:44, 14 September 2022

2022-09-14T07:44:25Z

←Older revision		Revision as of 07:44, 14 September 2022
Line 3:		Line 3:
	<StructureSection load='4d2r' size='340' side='right'caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='4d2r' size='340' side='right'caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4D2R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D2R FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [https://pdbe.org/4d2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [https://www.ebi.ac.uk/pdbsum/4d2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2r ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [~~http~~://pdbe.org/4d2r PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4d2r PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2r ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:[~~http~~://omim.org/entry/270450 270450]]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.<ref>PMID:14657428</ref> <ref>PMID:15928254</ref>	+	[[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:[https://omim.org/entry/270450 270450]]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.<ref>PMID:14657428</ref> <ref>PMID:15928254</ref>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref> When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref>	+	[[https://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref> When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 29:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Ballard P]]
-	[[Category: Ballard, P]]	+	[[Category: Bardelle C]]
-	[[Category: Bardelle, C]]	+	[[Category: Butterworth S]]
-	[[Category: Butterworth, S]]	+	[[Category: Colclough N]]
-	[[Category: Colclough, N]]	+	[[Category: Critchlow SE]]
-	[[Category: Critchlow~~, S E~~]]	+	[[Category: Debreczeni JE]]
-	[[Category: Debreczeni~~, J E~~]]	+	[[Category: Fairley G]]
-	[[Category: Fairley, G]]	+	[[Category: Fillery S]]
-	[[Category: Fillery, S]]	+	[[Category: Goodwin L]]
-	[[Category: Goodwin, L]]	+	[[Category: Graham MA]]
-	[[Category: Graham~~, M A~~]]	+	[[Category: Guichard S]]
-	[[Category: Guichard, S]]	+	[[Category: Hudson K]]
-	[[Category: Hudson, K]]	+	[[Category: Kettle JG]]
-	[[Category: Kettle~~, J G~~]]	+	[[Category: Mahmood A]]
-	[[Category: Mahmood, A]]	+	[[Category: Vincent J]]
-	[[Category: Vincent, J]]	+	[[Category: Ward RA]]
-	[[Category: Ward~~, R A~~]]	+	[[Category: Whittaker D]]
-	[[Category: Whittaker, D]]	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Oncology]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:23, 23 October 2019

2019-10-23T07:23:06Z

←Older revision		Revision as of 07:23, 23 October 2019
Line 1:		Line 1:

	==Human IGF in complex with a Dyrk1B inhibitor==		==Human IGF in complex with a Dyrk1B inhibitor==
-	<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>	+	<StructureSection load='4d2r' size='340' side='right'caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2R FirstGlance]. <br>		<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2R FirstGlance]. <br>
Line 30:		Line 30:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Ballard, P]]		[[Category: Ballard, P]]
Line 35:		Line 36:
	[[Category: Butterworth, S]]		[[Category: Butterworth, S]]
	[[Category: Colclough, N]]		[[Category: Colclough, N]]
-	[[Category: ~~Crichlow~~, S]]	+	[[Category: Critchlow, S E]]
	[[Category: Debreczeni, J E]]		[[Category: Debreczeni, J E]]
	[[Category: Fairley, G]]		[[Category: Fairley, G]]

OCA at 06:38, 4 April 2018

2018-04-04T06:38:40Z

←Older revision		Revision as of 06:38, 4 April 2018
Line 3:		Line 3:
	<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4d2r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D2R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2R FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4d2r]] 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=4D2R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2R FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</td></tr>
Line 22:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 4d2r" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4d2r" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Insulin-like growth factor receptor\|Insulin-like growth factor receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Ballard, P]]		[[Category: Ballard, P]]

OCA at 18:44, 1 February 2017

2017-02-01T18:44:06Z

←Older revision		Revision as of 18:44, 1 February 2017
Line 1:		Line 1:
		+
	==Human IGF in complex with a Dyrk1B inhibitor==		==Human IGF in complex with a Dyrk1B inhibitor==
	<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [http://www.ebi.ac.uk/pdbsum/4d2r 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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [http://pdbe.org/4d2r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [http://www.ebi.ac.uk/pdbsum/4d2r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2r ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	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 4d2r" style="background-color:#fffaf0;"></div>
-	==~~See Also==~~	+
-	*[[Insulin-like growth factor receptor\|Insulin-~~like growth factor receptor]]~~	+
	== References ==		== References ==
	<references/>		<references/>

OCA at 11:26, 30 April 2015

2015-04-30T11:26:02Z

←Older revision		Revision as of 11:26, 30 April 2015
Line 20:		Line 20:
	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>
		+
		+	==See Also==
		+	*[[Insulin-like growth factor receptor\|Insulin-like growth factor receptor]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:43, 22 April 2015

2015-04-22T12:43:56Z

←Older revision		Revision as of 12:43, 22 April 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Human IGF in complex with a Dyrk1B inhibitor==
		+	<StructureSection load='4d2r' size='340' side='right' caption='[[4d2r]], [[Resolution\|resolution]] 2.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4d2r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D2R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4D2R FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DYK:N-{2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]PHENYL}-4-(1H-PYRROLO[2,3-C]PYRIDIN-3-YL)PYRIMIDIN-2-AMINE'>DYK</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4d2s\|4d2s]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d2r RCSB], [http://www.ebi.ac.uk/pdbsum/4d2r PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:[http://omim.org/entry/270450 270450]]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.<ref>PMID:14657428</ref> <ref>PMID:15928254</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/IGF1R_HUMAN IGF1R_HUMAN]] Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref> When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.<ref>PMID:8257688</ref> <ref>PMID:1846292</ref> <ref>PMID:8452530</ref> <ref>PMID:7679099</ref> <ref>PMID:10579905</ref> <ref>PMID:10747872</ref> <ref>PMID:12138094</ref> <ref>PMID:12556535</ref> <ref>PMID:16831875</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response.

-	~~The entry 4d2r is ON HOLD~~	+	Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis.,Kettle JG, Ballard P, Bardelle C, Cockerill M, Colclough N, Critchlow SE, Debreczeni J, Fairley G, Fillery S, Graham MA, Goodwin L, Guichard S, Hudson K, Ward RA, Whittaker D J Med Chem. 2015 Mar 26;58(6):2834-44. doi: 10.1021/acs.jmedchem.5b00098. Epub, 2015 Mar 12. PMID:25738750<ref>PMID:25738750</ref>

-	~~Authors: Debreczeni~~, J.~~E., Kettle, J., Ballard, P., Bardelle, C., Butterworth,~~ S.~~, Colclough, N., Crichlow, S., Fairley, G., Fillery, S., Graham, M., Goodwin, L., Guichard, S., Hudson, K., Mahmood, A., Vincent, J., Ward, R.A., Whittaker, J~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Human IGF in complex with a Dyrk1B inhibitor~~	+	== References ==
-	[[Category: ~~Unreleased Structures~~]]	+	<references/>
-	[[Category: ~~Hudson~~, K]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Ballard, P]]
		+	[[Category: Bardelle, C]]
	[[Category: Butterworth, S]]		[[Category: Butterworth, S]]
		+	[[Category: Colclough, N]]
		+	[[Category: Crichlow, S]]
		+	[[Category: Debreczeni, J E]]
	[[Category: Fairley, G]]		[[Category: Fairley, G]]
	[[Category: Fillery, S]]		[[Category: Fillery, S]]
-	[[Category: Ward, R.A]]
-	[[Category: Vincent, J]]
-	[[Category: Mahmood, A]]
-	[[Category: Whittaker, J]]
-	[[Category: Colclough, N]]
	[[Category: Goodwin, L]]		[[Category: Goodwin, L]]
-	[[Category: ~~Ballard~~, ~~P]]~~	+	[[Category: Graham, M A]]
-	~~[[Category: Debreczeni, J.E]]~~	+
-	~~[[Category: Bardelle, C~~]]	+
	[[Category: Guichard, S]]		[[Category: Guichard, S]]
-	[[Category: ~~Graham~~, M]]	+	[[Category: Hudson, K]]
-	[[Category: ~~Crichlow~~, S]]	+	[[Category: Kettle, J G]]
-	[[Category: ~~Kettle~~, J]]	+	[[Category: Mahmood, A]]
		+	[[Category: Vincent, J]]
		+	[[Category: Ward, R A]]
		+	[[Category: Whittaker, D]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Oncology]]
		+	[[Category: Transferase]]

OCA at 13:42, 24 December 2014

2014-12-24T13:42:35Z

←Older revision		Revision as of 13:42, 24 December 2014
Line 6:		Line 6:

	Description: Human IGF in complex with a Dyrk1B inhibitor		Description: Human IGF in complex with a Dyrk1B inhibitor
		+	[[Category: Unreleased Structures]]
		+	[[Category: Hudson, K]]
		+	[[Category: Butterworth, S]]
		+	[[Category: Fairley, G]]
		+	[[Category: Fillery, S]]
		+	[[Category: Ward, R.A]]
		+	[[Category: Vincent, J]]
		+	[[Category: Mahmood, A]]
		+	[[Category: Whittaker, J]]
		+	[[Category: Colclough, N]]
		+	[[Category: Goodwin, L]]
		+	[[Category: Ballard, P]]
		+	[[Category: Debreczeni, J.E]]
		+	[[Category: Bardelle, C]]
		+	[[Category: Guichard, S]]
		+	[[Category: Graham, M]]
		+	[[Category: Crichlow, S]]
		+	[[Category: Kettle, J]]

OCA: Protected "4d2r" [edit=sysop:move=sysop]

2014-05-21T07:33:31Z

Protected "4d2r" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:33, 21 May 2014

OCA: New page: '''Unreleased structure''' The entry 4d2r is ON HOLD Authors: Debreczeni, J.E., Kettle, J., Ballard, P., Bardelle, C., Butterworth, S., Colclough, N., Crichlow, S., Fairley, G., Fillery...

2014-05-21T07:33:29Z

New page: '''Unreleased structure''' The entry 4d2r is ON HOLD Authors: Debreczeni, J.E., Kettle, J., Ballard, P., Bardelle, C., Butterworth, S., Colclough, N., Crichlow, S., Fairley, G., Fillery...

New page

'''Unreleased structure'''

The entry 4d2r is ON HOLD

Authors: Debreczeni, J.E., Kettle, J., Ballard, P., Bardelle, C., Butterworth, S., Colclough, N., Crichlow, S., Fairley, G., Fillery, S., Graham, M., Goodwin, L., Guichard, S., Hudson, K., Mahmood, A., Vincent, J., Ward, R.A., Whittaker, J.

Description: Human IGF in complex with a Dyrk1B inhibitor