View source for 9sqx


==Crystal structure of IL-17A in complex with compound 19==
<StructureSection load='9sqx' size='340' side='right'caption='[[9sqx]], [[Resolution|resolution]] 1.41&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sqx]] 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=9SQX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SQX 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]] 1.413&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JPS:~{N}-[(~{S})-cyclohexyl-[3-[(4-oxidanylidene-3~{H}-phthalazin-1-yl)methyl]-1~{H}-1,2,4-triazol-5-yl]methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide'>A1JPS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=9sqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sqx OCA], [https://pdbe.org/9sqx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sqx RCSB], [https://www.ebi.ac.uk/pdbsum/9sqx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sqx ProSAT]</span></td></tr>
</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 ==
The proinflammatory cytokine IL-17 is crucial for host defense but has also been linked to various inflammatory and autoimmune diseases. Antibody-based IL-17 inhibitors like secukinumab (Cosentyx) have demonstrated clinical success in psoriasis, psoriatic arthritis, and ankylosing spondylitis, sparking efforts to develop orally bioavailable small molecule alternatives. However, most small molecule IL-17 inhibitors failed in preclinical and clinical stages due to safety concerns and other challenges. This work describes the discovery of a 1,2,4-triazole scaffold that acts as an amide bioisostere. Its unique vector toward the Trp90 pocket, a key cavity for ligand binding, required the development of novel motifs. A structure-based library approach, considering the high plasticity of the Gln117 side chain, yielded structurally diverse Trp90 pocket binding motifs. The X-ray structures of the most potent hits guided subsequent optimization, resulting in triazole-based IL-17 inhibitors with low nanomolar cellular activity, which are promising leads for further development.

Harnessing Glutamine-117 Plasticity toward Structure-Based Identification of Triazole IL-17 Inhibitors.,Bauer MR, Velcicky J, Goetz A, Furet P, Nimsgern P, Tichkule R, Schlapbach A, Meyer A, Vogtle M, Rolando C, Lehmann H, Berst F, Riek S, Schmutz P, Lehmann S, Scheufler C, Rondeau JM, Burkhart C, Gommermann N, Knoepfel T J Med Chem. 2025 Dec 7. doi: 10.1021/acs.jmedchem.5c02794. PMID:41355177<ref>PMID:41355177</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9sqx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lehmann S]]
[[Category: Rondeau JM]]
[[Category: Scheufler C]]