8cdg

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Current revision (07:59, 6 December 2023) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 8cdg is ON HOLD until Paper Publication
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==Crystal structure of human IL-17A cytokine in complex with macrocycle==
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<StructureSection load='8cdg' size='340' side='right'caption='[[8cdg]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[8cdg]] 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=8CDG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CDG FirstGlance]. <br>
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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]] 2.9&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UTF:(9~{S},12~{R},19~{S})-9-[[4-[[(2~{S})-2-cyclohexyl-2-(2-phenylethanoylamino)ethanoyl]amino]phenyl]methyl]-12-methyl-7,10,13,21-tetrakis(oxidanylidene)-8,11,14,20-tetrazaspiro[4.17]docosane-19-carboxylic+acid'>UTF</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8cdg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cdg OCA], [https://pdbe.org/8cdg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cdg RCSB], [https://www.ebi.ac.uk/pdbsum/8cdg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cdg ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/IL17_HUMAN IL17_HUMAN] Induces stromal cells to produce proinflammatory and hematopoietic cytokines. Enhances the surface expression of ICAM1/intracellular adhesion molecule 1 in fibroblasts.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Knowledge of protein dynamics is fundamental to the understanding of biological processes, with NMR and 2D-IR spectroscopy being two of the principal methods for studying protein dynamics. Here, we combine these two methods to gain a new understanding of the complex mechanism of a cytokine:receptor interaction. The dynamic nature of many cytokines is now being recognised as a key property in the signalling mechanism. Interleukin-17s (IL-17) are proinflammatory cytokines which, if unregulated, are associated with serious autoimmune diseases such as psoriasis, and although there are several therapeutics on the market for these conditions, small molecule therapeutics remain elusive. Previous studies, exploiting crystallographic methods alone, have been unable to explain the dramatic differences in affinity observed between IL-17 dimers and their receptors, suggesting there are factors that cannot be fully explained by the analysis of static structures alone. Here, we show that the IL-17 family of cytokines have varying degrees of flexibility which directly correlates to their receptor affinities. Small molecule inhibitors of the cytokine:receptor interaction are usually thought to function by either causing steric clashes or structural changes. However, our results, supported by other biophysical methods, provide evidence for an alternate mechanism of inhibition, in which the small molecule rigidifies the protein, causing a reduction in receptor affinity. The results presented here indicate an induced fit model of cytokine:receptor binding, with the more flexible cytokines having a higher affinity. Our approach could be applied to other systems where the inhibition of a protein-protein interaction has proved intractable, for example due to the flat, featureless nature of the interface. Targeting allosteric sites which modulate protein dynamics, opens up new avenues for novel therapeutic development.
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Authors:
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Modulation of IL-17 backbone dynamics reduces receptor affinity and reveals a new inhibitory mechanism.,Shaw DJ, Waters LC, Strong SL, Schulze MED, Greetham GM, Towrie M, Parker AW, Prosser CE, Henry AJ, Lawson ADG, Carr MD, Taylor RJ, Hunt NT, Muskett FW Chem Sci. 2023 Jun 16;14(27):7524-7536. doi: 10.1039/d3sc00728f. eCollection 2023 , Jul 12. PMID:37449080<ref>PMID:37449080</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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<div class="pdbe-citations 8cdg" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Schulze M-S]]

Current revision

Crystal structure of human IL-17A cytokine in complex with macrocycle

PDB ID 8cdg

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