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<StructureSection load='4xss' size='340' side='right'caption='[[4xss]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='4xss' size='340' side='right'caption='[[4xss]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4xss]] is a 3 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=4XSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XSS FirstGlance]. <br>
<table><tr><td colspan='2'>[[4xss]] is a 3 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=4XSS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XSS FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 3&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3w11|3w11]], [[3w12|3w12]], [[3w13|3w13]], [[3w14|3w14]], [[4oga|4oga]], [[4xst|4xst]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IGF1, IBP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), INSR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4xss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xss OCA], [https://pdbe.org/4xss PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xss RCSB], [https://www.ebi.ac.uk/pdbsum/4xss PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xss 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=4xss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xss OCA], [http://pdbe.org/4xss PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xss RCSB], [http://www.ebi.ac.uk/pdbsum/4xss PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xss ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/IGF1_HUMAN IGF1_HUMAN]] Defects in IGF1 are the cause of insulin-like growth factor I deficiency (IGF1 deficiency) [MIM:[http://omim.org/entry/608747 608747]]. IGF1 deficiency is an autosomal recessive disorder characterized by growth retardation, sensorineural deafness and mental retardation. [[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:[http://omim.org/entry/262190 262190]]; also known as Mendenhall syndrome. RMS is a severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.<ref>PMID:2121734</ref> <ref>PMID:2365819</ref> <ref>PMID:8314008</ref> <ref>PMID:10443650</ref> <ref>PMID:12023989</ref> <ref>PMID:17201797</ref>  Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:[http://omim.org/entry/246200 246200]]; also known as Donohue syndrome. Leprechaunism represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.<ref>PMID:2365819</ref> <ref>PMID:12023989</ref> <ref>PMID:2834824</ref> <ref>PMID:2479553</ref> <ref>PMID:1607067</ref> <ref>PMID:1730625</ref> <ref>PMID:8326490</ref> <ref>PMID:8419945</ref> <ref>PMID:8188715</ref> <ref>PMID:7815442</ref> <ref>PMID:7538143</ref> <ref>PMID:8636294</ref> <ref>PMID:9299395</ref> <ref>PMID:9249867</ref> <ref>PMID:9703342</ref> <ref>PMID:12538626</ref> <ref>PMID:12970295</ref>  Defects in INSR may be associated with noninsulin-dependent diabetes mellitus (NIDDM) [MIM:[http://omim.org/entry/125853 125853]]; also known as diabetes mellitus type 2.<ref>PMID:1607076</ref> <ref>PMID:1470163</ref> <ref>PMID:7657032</ref>  Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 5 (HHF5) [MIM:[http://omim.org/entry/609968 609968]]. Familial hyperinsulinemic hypoglycemia [MIM:[http://omim.org/entry/256450 256450]], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.<ref>PMID:15161766</ref>  Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:[http://omim.org/entry/610549 610549]]. This syndrome is characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.  
[https://www.uniprot.org/uniprot/IGF1_HUMAN IGF1_HUMAN] Defects in IGF1 are the cause of insulin-like growth factor I deficiency (IGF1 deficiency) [MIM:[https://omim.org/entry/608747 608747]. IGF1 deficiency is an autosomal recessive disorder characterized by growth retardation, sensorineural deafness and mental retardation.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/IGF1_HUMAN IGF1_HUMAN]] The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in rat bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake.<ref>PMID:21076856</ref> [[http://www.uniprot.org/uniprot/INSR_HUMAN INSR_HUMAN]] Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, 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:8452530</ref> <ref>PMID:8276809</ref> <ref>PMID:9428692</ref> <ref>PMID:10207053</ref> <ref>PMID:12138094</ref> <ref>PMID:16314505</ref> <ref>PMID:16831875</ref> 
[https://www.uniprot.org/uniprot/IGF1_HUMAN IGF1_HUMAN] The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in rat bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake.<ref>PMID:21076856</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Kong GK-W]]
[[Category: Kong, G K.W]]
[[Category: Lawrence C]]
[[Category: Lawrence, C]]
[[Category: Lawrence MC]]
[[Category: Lawrence, M C]]
[[Category: Menting JG]]
[[Category: Menting, J G]]
[[Category: Cell surface receptor/immune system]]
[[Category: Ct peptide]]
[[Category: Hormone receptor-hormone-immune system complex]]
[[Category: Hormone-hormone receptor complex]]
[[Category: Insulin receptor]]
[[Category: Insulin-like growth factor receptor]]

Latest revision as of 10:48, 27 September 2023

Insulin-like growth factor I in complex with site 1 of a hybrid insulin receptor / Type 1 insulin-like growth factor receptorInsulin-like growth factor I in complex with site 1 of a hybrid insulin receptor / Type 1 insulin-like growth factor receptor

Structural highlights

4xss is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

IGF1_HUMAN Defects in IGF1 are the cause of insulin-like growth factor I deficiency (IGF1 deficiency) [MIM:608747. IGF1 deficiency is an autosomal recessive disorder characterized by growth retardation, sensorineural deafness and mental retardation.

Function

IGF1_HUMAN The insulin-like growth factors, isolated from plasma, are structurally and functionally related to insulin but have a much higher growth-promoting activity. May be a physiological regulator of [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblasts. Stimulates glucose transport in rat bone-derived osteoblastic (PyMS) cells and is effective at much lower concentrations than insulin, not only regarding glycogen and DNA synthesis but also with regard to enhancing glucose uptake.[1]

Publication Abstract from PubMed

The homodimeric insulin and type 1 insulin-like growth factor receptors (IR and IGF-1R) share a common architecture and each can bind all three ligands within the family: insulin and insulin-like growth factors I and II (IGF-I and IFG-II). The receptor monomers also assemble as heterodimers, the primary ligand-binding sites of which each comprise the first leucine-rich repeat domain (L1) of one receptor type and an alpha-chain C-terminal segment (alphaCT) of the second receptor type. We present here crystal structures of IGF-I bound to such a hybrid primary binding site and of a ligand-free version of an IR alphaCT peptide bound to an IR L1 plus cysteine-rich domain construct (IR310.T). These structures, refined at 3.0-A resolution, prove congruent to respective existing structures of insulin-complexed IR310.T and the intact apo-IR ectodomain. As such, they provide key missing links in the emerging, but sparse, repertoire of structures defining the receptor family.

Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors.,Menting JG, Lawrence CF, Kong GK, Margetts MB, Ward CW, Lawrence MC Structure. 2015 May 19. pii: S0969-2126(15)00174-4. doi:, 10.1016/j.str.2015.04.016. PMID:26027733[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Zoidis E, Ghirlanda-Keller C, Schmid C. Stimulation of glucose transport in osteoblastic cells by parathyroid hormone and insulin-like growth factor I. Mol Cell Biochem. 2011 Feb;348(1-2):33-42. doi: 10.1007/s11010-010-0634-z. Epub, 2010 Nov 13. PMID:21076856 doi:10.1007/s11010-010-0634-z
  2. ↑ Menting JG, Lawrence CF, Kong GK, Margetts MB, Ward CW, Lawrence MC. Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors. Structure. 2015 May 19. pii: S0969-2126(15)00174-4. doi:, 10.1016/j.str.2015.04.016. PMID:26027733 doi:http://dx.doi.org/10.1016/j.str.2015.04.016

4xss, resolution 3.00Å

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