1m7n

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<StructureSection load='1m7n' size='340' side='right'caption='[[1m7n]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='1m7n' size='340' side='right'caption='[[1m7n]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[1m7n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M7N FirstGlance]. <br>
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<table><tr><td colspan='2'>[[1m7n]] is a 2 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=1M7N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1M7N FirstGlance]. <br>
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</td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Transferase Transferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</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=1m7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m7n OCA], [https://pdbe.org/1m7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m7n RCSB], [https://www.ebi.ac.uk/pdbsum/1m7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m7n 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=1m7n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m7n OCA], [https://pdbe.org/1m7n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1m7n RCSB], [https://www.ebi.ac.uk/pdbsum/1m7n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1m7n ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[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>
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[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 ==
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[[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>
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[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 ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</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=1m7n ConSurf].
</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=1m7n ConSurf].
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== Publication Abstract from PubMed ==
 
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The x-ray structure of the unactivated kinase domain of insulin-like growth factor-1 receptor (IGFRK-0P) is reported here at 2.7 A resolution. IGFRK-0P is composed of two lobes connected by a hinge region. The N-terminal lobe of the kinase is a twisted beta-sheet flanked by a single helix, and the C-terminal lobe comprises eight alpha-helices and four short beta-strands. The ATP binding pocket and the catalytic center reside at the interface of the two lobes. Despite the overall similarity to other receptor tyrosine kinases, three notable conformational modifications are observed: 1) this kinase adopts a more closed structure, with its two lobes rotated further toward each other; 2) the conformation of the proximal end of the activation loop (residues 1121-1129) is different; 3) the orientation of the nucleotide-binding loop is altered. Collectively, these alterations lead to a different ATP-binding pocket that might impact on inhibitor designs for IGFRK-0P. Two molecules of IGFRK-0P are seen in the asymmetric unit; they are associated as a dimer with their ATP binding clefts facing each other. The ordered N terminus of one monomer approaches the active site of the other, suggesting that the juxtamembrane region of one molecule could come into close proximity to the active site of the other.
 
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Crystal structure of the Apo, unactivated insulin-like growth factor-1 receptor kinase. Implication for inhibitor specificity.,Munshi S, Kornienko M, Hall DL, Reid JC, Waxman L, Stirdivant SM, Darke PL, Kuo LC J Biol Chem. 2002 Oct 11;277(41):38797-802. Epub 2002 Jul 22. PMID:12138114<ref>PMID:12138114</ref>
 
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
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</div>
 
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<div class="pdbe-citations 1m7n" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Transferase]]
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[[Category: Kuo L]]
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[[Category: Kuo, L]]
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[[Category: Munshi S]]
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[[Category: Munshi, S]]
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Current revision

Crystal Structure of Unactivated APO Insulin-like Growth Factor-1 Receptor Kinase Domain

PDB ID 1m7n

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