5kqv: Difference between revisions

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<StructureSection load='5kqv' size='340' side='right'caption='[[5kqv]], [[Resolution|resolution]] 4.40&Aring;' scene=''>
<StructureSection load='5kqv' size='340' side='right'caption='[[5kqv]], [[Resolution|resolution]] 4.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5kqv]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3w14 3w14]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KQV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KQV FirstGlance]. <br>
<table><tr><td colspan='2'>[[5kqv]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3w14 3w14]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KQV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KQV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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]] 4.4&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zxb|4zxb]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">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=5kqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kqv OCA], [https://pdbe.org/5kqv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kqv RCSB], [https://www.ebi.ac.uk/pdbsum/5kqv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kqv ProSAT]</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=5kqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kqv OCA], [http://pdbe.org/5kqv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kqv RCSB], [http://www.ebi.ac.uk/pdbsum/5kqv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kqv ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[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.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/INS_BOVIN INS_BOVIN]] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver. [[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/INS_BOVIN INS_BOVIN] Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</StructureSection>
</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
[[Category: Croll, T I]]
[[Category: Croll TI]]
[[Category: Lawrence, M C]]
[[Category: Lawrence MC]]
[[Category: Smith, B J]]
[[Category: Smith BJ]]
[[Category: Cell surface receptor/immune system]]
[[Category: Ct peptide]]
[[Category: Hormone-hormone receptor-immune system complex]]
[[Category: Insulin receptor]]
[[Category: Ir ectodomain]]

Latest revision as of 13:51, 27 September 2023

Insulin receptor ectodomain construct comprising domains L1,CR,L2, FnIII-1 and alphaCT peptide in complex with bovine insulin and FAB 83-14 (REVISED STRUCTURE)Insulin receptor ectodomain construct comprising domains L1,CR,L2, FnIII-1 and alphaCT peptide in complex with bovine insulin and FAB 83-14 (REVISED STRUCTURE)

Structural highlights

5kqv is a 10 chain structure with sequence from Bos taurus, Homo sapiens and Mus musculus. This structure supersedes the now removed PDB entry 3w14. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 4.4Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

INS_BOVIN Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.

Publication Abstract from PubMed

Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alphaCT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.

How insulin engages its primary binding site on the insulin receptor.,Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Zakova L, Kletvikova E, Jiracek J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC Nature. 2013 Jan 10;493(7431):241-5. doi: 10.1038/nature11781. PMID:23302862[1]

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

See Also

References

  1. ↑ Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong GK, Smith BJ, Watson CJ, Zakova L, Kletvikova E, Jiracek J, Chan SJ, Steiner DF, Dodson GG, Brzozowski AM, Weiss MA, Ward CW, Lawrence MC. How insulin engages its primary binding site on the insulin receptor. Nature. 2013 Jan 10;493(7431):241-5. doi: 10.1038/nature11781. PMID:23302862 doi:10.1038/nature11781

5kqv, resolution 4.40Å

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