View source for 28zr


==Crystal structure of human DHX8 in complex with compound 51 and ADP==
<StructureSection load='28zr' size='340' side='right'caption='[[28zr]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[28zr]] 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=28ZR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=28ZR 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]] 2.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1J1J:2-[(2~{S})-1-[4-(propan-2-ylamino)phenyl]propan-2-yl]sulfanylpyridine-3-carboxylic+acid'>A1J1J</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=28zr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=28zr OCA], [https://pdbe.org/28zr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=28zr RCSB], [https://www.ebi.ac.uk/pdbsum/28zr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=28zr ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/DHX8_HUMAN DHX8_HUMAN] Facilitates nuclear export of spliced mRNA by releasing the RNA from the spliceosome.<ref>PMID:8608946</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human DHX8 is a spliceosomal DEAH-box RNA helicase involved in releasing mRNA from the spliceosome and crucial in ensuring splicing fidelity. DHX8 was identified as a promising therapeutic oncology target due to its role in regulating stress-adaptive gene expression, including HSF1-dependent transcription, while having broader transcriptional effects in cells under oncogenic stress. We report the discovery of novel RNA-competitive DHX8 inhibitors based on a 2-(phenethylthio)nicotinic acid scaffold, which were optimized using a structure-guided design approach, following a biophysical fragment screen. This yielded compound 53 with nanomolar biochemical potency, good in vitro PK, and activity in a cellular target engagement assay. Optimizing inhibitor binding between Arg647 and the nonconserved His693, coupled with extending into a pocket in the DHX8 Winged-Helix domain, was crucial for potency improvement. By binding in the Winged-Helix domain, these inhibitors restrict the helicase domain's conformational plasticity, stabilizing a closed, inactive conformation while sterically blocking ssRNA translocation.

Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8.,Read BJ, Ewens C, Gigante F, Thomas J, Felisberto-Rodrigues C, Alvarez Peres S, Tighe C, de Las Heras Ruiz E, Schiemann K, Malcolm AG, McAndrew PC, Stubbs M, Patani H, Costa HDS, Stoodley K, Pickard L, Busch M, Gunnell E, Silva S, Knopp A, Hallett ST, Augustin M, Lammens A, Carter M, Meniconi M, Ballarotto M, Ainsley J, Meister P, Sethi D, Burke R, Scarpino A, Le Bihan YV, Gradler U, Blagg J, Workman P, Clarke PA, Blum A, Esdar C, Bhalay G, van Montfort RLM J Med Chem. 2026 Aug 13;69(15):18277-18299. doi: 10.1021/acs.jmedchem.6c00732. PMID:42593941<ref>PMID:42593941</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 28zr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Felisberto-Rodrigues C]]
[[Category: Le Bihan Y-V]]
[[Category: Silva STN]]
[[Category: Van Montfort RLM]]