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| | ==Crystal structure of human interleukin 6 in complex with a modified nucleotide aptamer (SOMAMER SL1025), FORM 2== | | ==Crystal structure of human interleukin 6 in complex with a modified nucleotide aptamer (SOMAMER SL1025), FORM 2== |
| - | <StructureSection load='4ni9' size='340' side='right' caption='[[4ni9]], [[Resolution|resolution]] 2.55Å' scene=''> | + | <StructureSection load='4ni9' size='340' side='right'caption='[[4ni9]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ni9]] is a 4 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=4NI9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NI9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ni9]] is a 4 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=4NI9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NI9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2JU:2-DEOXY-5-[(NAPHTHALEN-1-YLMETHYL)CARBAMOYL]URIDINE+5-(DIHYDROGEN+PHOSPHATE)'>2JU</scene>, <scene name='pdbligand=A2M:2-O-METHYLADENOSINE+5-(DIHYDROGEN+PHOSPHATE)'>A2M</scene>, <scene name='pdbligand=DUZ:5-(BENZYLCARBAMOYL)-2-DEOXYURIDINE+5-(DIHYDROGEN+PHOSPHATE)'>DUZ</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=OMC:O2-METHYLYCYTIDINE-5-MONOPHOSPHATE'>OMC</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</scene>, <scene name='pdbligand=UPE:2-DEOXY-5-[(2-PHENYLETHYL)CARBAMOYL]URIDINE+5-(DIHYDROGEN+PHOSPHATE)'>UPE</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=2JU:2-DEOXY-5-[(NAPHTHALEN-1-YLMETHYL)CARBAMOYL]URIDINE+5-(DIHYDROGEN+PHOSPHATE)'>2JU</scene>, <scene name='pdbligand=A2M:2-O-METHYLADENOSINE+5-(DIHYDROGEN+PHOSPHATE)'>A2M</scene>, <scene name='pdbligand=DUZ:5-(BENZYLCARBAMOYL)-2-DEOXYURIDINE+5-(DIHYDROGEN+PHOSPHATE)'>DUZ</scene>, <scene name='pdbligand=OMC:O2-METHYLYCYTIDINE-5-MONOPHOSPHATE'>OMC</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</scene>, <scene name='pdbligand=UPE:2-DEOXY-5-[(2-PHENYLETHYL)CARBAMOYL]URIDINE+5-(DIHYDROGEN+PHOSPHATE)'>UPE</scene></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=4ni9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ni9 OCA], [https://pdbe.org/4ni9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ni9 RCSB], [https://www.ebi.ac.uk/pdbsum/4ni9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ni9 ProSAT]</span></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ni7|4ni7]]</td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IL6, IFNB2 ([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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ni9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ni9 OCA], [http://pdbe.org/4ni9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ni9 RCSB], [http://www.ebi.ac.uk/pdbsum/4ni9 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/IL6_HUMAN IL6_HUMAN]] Genetic variations in IL6 are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:[http://omim.org/entry/604302 604302]]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Note=A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men. | + | [https://www.uniprot.org/uniprot/IL6_HUMAN IL6_HUMAN] Genetic variations in IL6 are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:[https://omim.org/entry/604302 604302]. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Note=A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/IL6_HUMAN IL6_HUMAN]] Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance. | + | [https://www.uniprot.org/uniprot/IL6_HUMAN IL6_HUMAN] Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Interleukin|Interleukin]] | + | *[[Interleukin 3D structures|Interleukin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Clifton, M C]] | + | [[Category: Large Structures]] |
| - | [[Category: Davies, D]] | + | [[Category: Clifton MC]] |
| - | [[Category: Edwards, T]] | + | [[Category: Davies D]] |
| - | [[Category: Gelinas, A]] | + | [[Category: Edwards T]] |
| - | [[Category: Jarvis, T]] | + | [[Category: Gelinas A]] |
| - | [[Category: Cytokine-dna complex]]
| + | [[Category: Jarvis T]] |
| - | [[Category: Selex]]
| + | |
| - | [[Category: Somamer]]
| + | |
| Structural highlights
4ni9 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
IL6_HUMAN Genetic variations in IL6 are associated with susceptibility to rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302. An inflammatory articular disorder with systemic-onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Note=A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men.
Function
IL6_HUMAN Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance.
Publication Abstract from PubMed
IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Ralpha and gp130. Due to its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (Slow Off-rate Modified Aptamers) that bind IL-6 and inhibit its biological activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here we report the co-crystal structure of a high-affinity SOMAmer (Kd=0.20 nM) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Ralpha and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd=270 nM). A single substitution from our diverse modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd=7.4 nM). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer:IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets.
Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand.,Gelinas AD, Davies DR, Edwards TE, Rohloff JC, Carter JD, Zhang C, Gupta S, Ishikawa Y, Hirota M, Nakaishi Y, Jarvis TC, Janjic N J Biol Chem. 2014 Jan 12. PMID:24415767[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gelinas AD, Davies DR, Edwards TE, Rohloff JC, Carter JD, Zhang C, Gupta S, Ishikawa Y, Hirota M, Nakaishi Y, Jarvis TC, Janjic N. Crystal Structure of Interleukin-6 in Complex with a Modified Nucleic Acid Ligand. J Biol Chem. 2014 Jan 12. PMID:24415767 doi:http://dx.doi.org/10.1074/jbc.M113.532697
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