7amg
From Proteopedia
(Difference between revisions)
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<StructureSection load='7amg' size='340' side='right'caption='[[7amg]], [[Resolution|resolution]] 3.18Å' scene=''> | <StructureSection load='7amg' size='340' side='right'caption='[[7amg]], [[Resolution|resolution]] 3.18Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'> | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AMG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AMG FirstGlance]. <br> |
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.18Å</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]] 3.18Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RMQ:(3~{R})-4-[4-[[(2~{S})-2-[[2,2-bis(fluoranyl)-2-phenyl-ethanoyl]amino]-3-(2-chlorophenyl)propanoyl]amino]phenyl]-3-[[(2~{S})-3-methyl-2-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethanoylamino]butanoyl]amino]butanoic+acid'>RMQ</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RMQ:(3~{R})-4-[4-[[(2~{S})-2-[[2,2-bis(fluoranyl)-2-phenyl-ethanoyl]amino]-3-(2-chlorophenyl)propanoyl]amino]phenyl]-3-[[(2~{S})-3-methyl-2-[2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]ethoxy]ethanoylamino]butanoyl]amino]butanoic+acid'>RMQ</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=7amg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7amg OCA], [https://pdbe.org/7amg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7amg RCSB], [https://www.ebi.ac.uk/pdbsum/7amg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7amg 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=7amg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7amg OCA], [https://pdbe.org/7amg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7amg RCSB], [https://www.ebi.ac.uk/pdbsum/7amg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7amg ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == Function == | ||
| - | [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. | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | 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. | ||
| - | |||
| - | 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> | ||
| - | |||
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 7amg" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Interleukin 3D structures|Interleukin 3D structures]] | *[[Interleukin 3D structures|Interleukin 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Andrews MD]] | [[Category: Andrews MD]] | ||
Current revision
IL-17A in complex with small molecule modulators
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Categories: Large Structures | Andrews MD | Dack KN | Hakansson M | Kimbung R | Lambert M | Logan D | Walse UB | De Groot MJ
