28ZI
Crystal structure of human DHX8 in complex with compound 1 and ADP
This is a non-PDB format compatible entry.
Summary for 28ZI
| Entry DOI | 10.2210/pdb28zi/pdb |
| Descriptor | ATP-dependent RNA helicase DHX8, ADENOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total) |
| Functional Keywords | helicase, rna, splicing, inhibitor, cancer, rna binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 316629.20 |
| Authors | Felisberto-Rodrigues, C.,Silva, S.T.N.,Le Bihan, Y.-V.,van Montfort, R.L.M. (deposition date: 2026-03-03, release date: 2026-09-02) |
| Primary citation | Read, B.J.,Ewens, C.,Gigante, F.,Thomas, J.,Felisberto-Rodrigues, C.,Alvarez Peres, S.,Tighe, C.,de Las Heras Ruiz, E.,Schiemann, K.,Malcolm, A.G.,McAndrew, P.C.,Stubbs, M.,Patani, H.,Costa, H.D.S.,Stoodley, K.,Pickard, L.,Busch, M.,Gunnell, E.,Silva, S.,Knopp, A.,Hallett, S.T.,Augustin, M.,Lammens, A.,Carter, M.,Meniconi, M.,Ballarotto, M.,Ainsley, J.,Meister, P.,Sethi, D.,Burke, R.,Scarpino, A.,Le Bihan, Y.V.,Gradler, U.,Blagg, J.,Workman, P.,Clarke, P.A.,Blum, A.,Esdar, C.,Bhalay, G.,van Montfort, R.L.M. Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8. J.Med.Chem., 69:18277-18299, 2026 Cited by PubMed Abstract: 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. PubMed: 42593941DOI: 10.1021/acs.jmedchem.6c00732 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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