7ama: Difference between revisions
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==IL-17A in complex with small molecule modulators== | ==IL-17A in complex with small molecule modulators== | ||
<StructureSection load='7ama' size='340' side='right'caption='[[7ama]]' scene=''> | <StructureSection load='7ama' size='340' side='right'caption='[[7ama]], [[Resolution|resolution]] 2.48Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>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> | <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> | ||
</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> | </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> | ||
<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 == | |||
[[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 7ama" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Andrews | [[Category: Andrews, M D]] | ||
[[Category: Dack | [[Category: Dack, K N]] | ||
[[Category: Hakansson M]] | [[Category: Groot, M J.de]] | ||
[[Category: Kimbung R]] | [[Category: Hakansson, M]] | ||
[[Category: Lambert M]] | [[Category: Kimbung, R]] | ||
[[Category: Logan D]] | [[Category: Lambert, M]] | ||
[[Category: Walse | [[Category: Logan, D]] | ||
[[Category: | [[Category: Walse, U B]] | ||
[[Category: Immune system]] | |||
[[Category: Interleukin il-17a inhibitor receptor]] | |||
