3d94

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (08:58, 30 October 2024) (edit) (undo)
 
(8 intermediate revisions not shown.)
Line 1: Line 1:
-
{{Seed}}
 
-
[[Image:3d94.png|left|200px]]
 
-
<!--
+
==Crystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIP==
-
The line below this paragraph, containing "STRUCTURE_3d94", creates the "Structure Box" on the page.
+
<StructureSection load='3d94' size='340' side='right'caption='[[3d94]], [[Resolution|resolution]] 2.30&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'>[[3d94]] 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=3D94 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D94 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]] 2.3&#8491;</td></tr>
-
-->
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=D94:3-[CIS-3-(4-METHYLPIPERAZIN-1-YL)CYCLOBUTYL]-1-(2-PHENYLQUINOLIN-7-YL)IMIDAZO[1,5-A]PYRAZIN-8-AMINE'>D94</scene>, <scene name='pdbligand=MHO:S-OXYMETHIONINE'>MHO</scene></td></tr>
-
{{STRUCTURE_3d94| PDB=3d94 | SCENE= }}
+
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3d94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d94 OCA], [https://pdbe.org/3d94 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d94 RCSB], [https://www.ebi.ac.uk/pdbsum/3d94 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d94 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/d9/3d94_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=3d94 ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)- imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.
-
===Crystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIP===
+
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor.,Wu J, Li W, Craddock BP, Foreman KW, Mulvihill MJ, Ji QS, Miller WT, Hubbard SR EMBO J. 2008 Jul 23;27(14):1985-94. Epub 2008 Jun 19. PMID:18566589<ref>PMID:18566589</ref>
 +
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 +
</div>
 +
<div class="pdbe-citations 3d94" style="background-color:#fffaf0;"></div>
-
<!--
+
==See Also==
-
The line below this paragraph, {{ABSTRACT_PUBMED_18566589}}, 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 18566589 is the PubMed ID number.
+
== References ==
-
-->
+
<references/>
-
{{ABSTRACT_PUBMED_18566589}}
+
__TOC__
-
 
+
</StructureSection>
-
==Disease==
+
-
Known disease associated with this structure: Insulin-like growth factor I, resistance to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147370 147370]]
+
-
 
+
-
==About this Structure==
+
-
3D94 is a 1 chain 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=3D94 OCA].
+
-
 
+
-
==Reference==
+
-
<ref group="xtra">PMID:18566589</ref><references group="xtra"/>
+
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Hubbard, S R.]]
+
[[Category: Large Structures]]
-
[[Category: Li, W.]]
+
[[Category: Hubbard SR]]
-
[[Category: Miller, W T.]]
+
[[Category: Li W]]
-
[[Category: Wu, J.]]
+
[[Category: Miller WT]]
-
[[Category: Atp-binding]]
+
[[Category: Wu J]]
-
[[Category: Glycoprotein]]
+
-
[[Category: Igf1rk]]
+
-
[[Category: Inhibitor]]
+
-
[[Category: Membrane]]
+
-
[[Category: Nucleotide-binding]]
+
-
[[Category: Phosphoprotein]]
+
-
[[Category: Pqip]]
+
-
[[Category: Receptor tyrosine kinase]]
+
-
[[Category: Transferase]]
+
-
[[Category: Transmembrane]]
+
-
[[Category: Tyrosine-protein kinase]]
+
-
 
+
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Feb 16 12:11:47 2009''
+

Current revision

Crystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIP

PDB ID 3d94

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3d94"
Personal tools