View source for 9sr8


==Crystal structure of IL-17A in complex with compound 22==
<StructureSection load='9sr8' size='340' side='right'caption='[[9sr8]], [[Resolution|resolution]] 2.56&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sr8]] 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=9SR8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SR8 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]] 2.565&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JPU:~{N}-[(~{S})-[3-[[7-bromanyl-3-methyl-2,4-bis(oxidanylidene)quinazolin-1-yl]methyl]-1~{H}-1,2,4-triazol-5-yl]-cyclohexyl-methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide'>A1JPU</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=9sr8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sr8 OCA], [https://pdbe.org/9sr8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sr8 RCSB], [https://www.ebi.ac.uk/pdbsum/9sr8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sr8 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 9sr8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Lehmann S]]
[[Category: Rondeau JM]]
[[Category: Scheufler C]]