3f5p: Difference between revisions

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-{{Seed}}
-[[Image:3f5p.jpg|left|200px]]
-<!--
+==Complex Structure of Insulin-like Growth Factor Receptor and 3-Cyanoquinoline Inhibitor==
-The line below this paragraph, containing "STRUCTURE_3f5p", creates the "Structure Box" on the page.
+<StructureSection load='3f5p' size='340' side='right'caption='[[3f5p]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3f5p]] is a 16 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=3F5P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3F5P FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=741:4-[[3-CHLORO-4-(1-METHYLIMIDAZOL-2-YL)SULFANYL-PHENYL]AMINO]-7-[3-(2-HYDROXYETHYL-METHYL-AMINO)PROPOXY]-6-METHOXY-QUINOLINE-3-CARBONITRILE'>741</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-{{STRUCTURE_3f5p|  PDB=3f5p  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3f5p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3f5p OCA], [https://pdbe.org/3f5p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3f5p RCSB], [https://www.ebi.ac.uk/pdbsum/3f5p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3f5p ProSAT]</span></td></tr>
+</table>
+== 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>
+== 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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f5/3f5p_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3f5p ConSurf].
+<div style="clear:both"></div>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. Inhibitors of this receptor are believed to provide a new target in cancer therapy. We previously reported an isoquinolinedione series of IGF-1R inhibitors. Now we have identified a series of 3-cyanoquinoline compounds that are low nanomolar inhibitors of IGF-1R. The strategies, synthesis, and SAR behind the cyanoquinoline scaffold will be discussed.
-===Complex Structure of Insulin-like Growth Factor Receptor and 3-Cyanoquinoline Inhibitor===
+Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment.,Miller LM, Mayer SC, Berger DM, Boschelli DH, Boschelli F, Di L, Du X, Dutia M, Floyd MB, Johnson M, Kenny CH, Krishnamurthy G, Moy F, Petusky S, Tkach D, Torres N, Wu B, Xu W Bioorg Med Chem Lett. 2009 Jan 1;19(1):62-6. Epub 2008 Nov 17. PMID:19041240<ref>PMID:19041240</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3f5p" style="background-color:#fffaf0;"></div>
-<!--
+==See Also==
-The line below this paragraph, {{ABSTRACT_PUBMED_19041240}}, adds the Publication Abstract to the page
+*[[Insulin-like growth factor receptor|Insulin-like growth factor receptor]]
-(as it appears on PubMed at http://www.pubmed.gov), where 19041240 is the PubMed ID number.
+== References ==
--->
+<references/>
-{{ABSTRACT_PUBMED_19041240}}
+__TOC__
+</StructureSection>
-==Disease==
-Known disease associated with this structure: Intrauterine and postnatal growth retardation OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147370 147370]]
-==About this Structure==
-F5P is a [[Single protein]] structure of 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=3F5P OCA].
-==Reference==
-Lead identification to generate 3-cyanoquinoline inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment., Miller LM, Mayer SC, Berger DM, Boschelli DH, Boschelli F, Di L, Du X, Dutia M, Floyd MB, Johnson M, Kenny CH, Krishnamurthy G, Moy F, Petusky S, Tkach D, Torres N, Wu B, Xu W, Bioorg Med Chem Lett. 2009 Jan 1;19(1):62-6. Epub 2008 Nov 17. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/19041240 19041240]
-Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment., Mayer SC, Banker AL, Boschelli F, Di L, Johnson M, Kenny CH, Krishnamurthy G, Kutterer K, Moy F, Petusky S, Ravi M, Tkach D, Tsou HR, Xu W, Bioorg Med Chem Lett. 2008 Jun 15;18(12):3641-5. Epub 2008 Apr 25. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18501599 18501599]
 [[Category: Homo sapiens]]
-[[Category: Receptor protein-tyrosine kinase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Berger DM]]
-[[Category: Pdbx_ordinal=, <PDBx:audit_author.]]
+[[Category: Boschelli DH]]
-[[Category: Atp-binding]]
+[[Category: Boschelli F]]
-[[Category: Cleavage on pair of basic residue]]
+[[Category: Mayer SC]]
-[[Category: Disease mutation]]
+[[Category: Miller LM]]
-[[Category: Glycoprotein]]
+[[Category: Xu W]]
-[[Category: Igf-1r]]
-[[Category: Membrane]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]
-[[Category: Protein-inhibitor complex]]
-[[Category: Receptor]]
-[[Category: Transferase]]
-[[Category: Transmembrane]]
-[[Category: Tyrosine kinase]]
-[[Category: Tyrosine-protein kinase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan  7 20:04:46 2009''