9MJW
Crystal structure of WRN helicase with bound allosteric fragment 3.
This is a non-PDB format compatible entry.
Summary for 9MJW
| Entry DOI | 10.2210/pdb9mjw/pdb |
| Descriptor | Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, ZINC ION, 6-chloro-7-methyl-1lambda~6~,2,4-benzothiadiazine-1,1,3(2H,4H)-trione, ... (4 entities in total) |
| Functional Keywords | wrn, werner, helicase, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 50792.99 |
| Authors | Palte, R.L.,Koglin, M.,Maskos, K.,Tauchert, M. (deposition date: 2024-12-16, release date: 2026-01-14, Last modification date: 2026-01-21) |
| Primary citation | Palte, R.L.,Mandal, M.,Sikorska, J.,Villafania, A.B.,Rickard, M.M.,Bauer, R.J.,Buevich, A.V.,Chai, X.,He, J.,Hussain, Z.,Koglin, M.,MacDonald, H.B.,Mansueto, M.S.,Maskos, K.,Methot, J.L.,Robustelli, J.,Soriano, A.,Tauchert, M.J.,Tyagarajan, S.,Zhang, M.,Klein, D.J.,Hicks, J.D.,McLaren, D.G.,Gabelli, S.B.,Wyss, D.F. WRN structural flexibility showcased through fragment-based lead discovery of inhibitors. Nat Commun, 17:79-79, 2026 Cited by PubMed Abstract: WRN helicase is an established synthetic lethal target for inhibition in the treatment of microsatellite instability-high (MSI-H) and mismatch repair deficient (MMRd) cancers. The identification of helicase inhibitors is challenging as high-throughput biochemical screening campaigns typically return few validated hits that are often inactive in cell-based assays. Herein, we highlight the power of non-covalent fragment-based lead discovery in locating new druggable allosteric sites on WRN, enabling us to bypass the challenging behavior of WRN during high-throughput screening hampering hit identification. During the fragment optimization process, structures of WRN with key prioritized fragments reveal multiple conformations of WRN with significant domain rotations up to 180°, including a WRN conformation not previously described. Rooted in a combination of biochemical, biophysical, and structural approaches, we present the detailed analyses of optimized chemical matter evolved from screening hits and the unique ability of WRN to accommodate diverse conformations as detailed by structural characterization. PubMed: 41484101DOI: 10.1038/s41467-025-66768-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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