7u23
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Single-chain LCDV-1 viral insulin-like peptide bound to IGF-1R ectodomain, leucine-zippered form== | |
| + | <StructureSection load='7u23' size='340' side='right'caption='[[7u23]], [[Resolution|resolution]] 4.60Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7u23]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lymphocystis_disease_virus_1 Lymphocystis disease virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U23 FirstGlance]. <br> | ||
| + | </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=7u23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u23 OCA], [https://pdbe.org/7u23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u23 RCSB], [https://www.ebi.ac.uk/pdbsum/7u23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u23 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism. | ||
| - | + | Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist.,Moreau F, Kirk NS, Zhang F, Gelfanov V, List EO, Chrudinova M, Venugopal H, Lawrence MC, Jimenez V, Bosch F, Kopchick JJ, DiMarchi RD, Altindis E, Ronald Kahn C Nat Commun. 2022 Nov 5;13(1):6700. doi: 10.1038/s41467-022-34391-6. PMID:36335114<ref>PMID:36335114</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 7u23" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lymphocystis disease virus 1]] | ||
| + | [[Category: Kirk NS]] | ||
| + | [[Category: Lawrence MC]] | ||
Revision as of 20:05, 16 November 2022
Single-chain LCDV-1 viral insulin-like peptide bound to IGF-1R ectodomain, leucine-zippered form
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