7ama

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<StructureSection load='7ama' size='340' side='right'caption='[[7ama]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
<StructureSection load='7ama' size='340' side='right'caption='[[7ama]], [[Resolution|resolution]] 2.48&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7ama]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AMA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMA FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7ama]] 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=7AMA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMA FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RMK:~{N}-[(2~{S})-1,1-dicyclopropyl-3-[[4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)phenyl]amino]-3-oxidanylidene-propan-2-yl]-2-propan-2-yl-pyrazole-3-carboxamide'>RMK</scene></td></tr>
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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]] 2.48&#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=RMK:~{N}-[(2~{S})-1,1-dicyclopropyl-3-[[4-(3,5-dimethyl-1~{H}-pyrazol-4-yl)phenyl]amino]-3-oxidanylidene-propan-2-yl]-2-propan-2-yl-pyrazole-3-carboxamide'>RMK</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=7ama FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ama OCA], [https://pdbe.org/7ama PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ama RCSB], [https://www.ebi.ac.uk/pdbsum/7ama PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ama ProSAT]</span></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=7ama FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ama OCA], [https://pdbe.org/7ama PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ama RCSB], [https://www.ebi.ac.uk/pdbsum/7ama PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ama ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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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[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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Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.
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Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.,Andrews MD, Dack KN, de Groot MJ, Lambert M, Sennbro CJ, Larsen M, Stahlhut M J Med Chem. 2022 Jul 14;65(13):8828-8842. doi: 10.1021/acs.jmedchem.2c00422. Epub, 2022 Jun 29. PMID:35767390<ref>PMID:35767390</ref>
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==See Also==
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*[[Interleukin 3D structures|Interleukin 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7ama" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Andrews, M D]]
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[[Category: Andrews MD]]
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[[Category: Dack, K N]]
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[[Category: Dack KN]]
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[[Category: Groot, M J.de]]
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[[Category: Hakansson M]]
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[[Category: Hakansson, M]]
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[[Category: Kimbung R]]
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[[Category: Kimbung, R]]
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[[Category: Lambert M]]
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[[Category: Lambert, M]]
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[[Category: Logan D]]
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[[Category: Logan, D]]
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[[Category: Walse UB]]
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[[Category: Walse, U B]]
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[[Category: De Groot MJ]]
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[[Category: Immune system]]
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[[Category: Interleukin il-17a inhibitor receptor]]
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Revision as of 07:45, 1 May 2024

IL-17A in complex with small molecule modulators

PDB ID 7ama

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