9mk1
Crystal structure of WRN helicase with bound compound 6
Structural highlights
DiseaseWRN_HUMAN Defects in WRN are a cause of Werner syndrome (WRN) [MIM:277700. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins.[1] Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:114500. FunctionWRN_HUMAN Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).[2] [3] [4] [5] [6] Publication Abstract from PubMedWRN 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 degrees , 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. WRN structural flexibility showcased through fragment-based lead discovery of inhibitors.,Palte RL, Mandal M, Sikorska J, Villafania AB, Rickard MM, Bauer RJ, Buevich AV, Chai X, He J, Hussain Z, Koglin M, MacDonald HB, Mansueto MS, Maskos K, Methot JL, Robustelli J, Soriano A, Tauchert MJ, Tyagarajan S, Zhang M, Klein DJ, Hicks JD, McLaren DG, Gabelli SB, Wyss DF Nat Commun. 2026 Jan 3;17(1):79. doi: 10.1038/s41467-025-66768-8. PMID:41484101[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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