9hlt | pdb_00009hlt
Crystal structure of human TRF1 TRFH domain in complex with compound 13
Structural highlights
FunctionTERF1_HUMAN Binds the telomeric double-stranded TTAGGG repeat and negatively regulates telomere length. Involved in the regulation of the mitotic spindle. Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways.[1] Publication Abstract from PubMedTRF1 is a subunit of the shelterin complex that binds to and protects the linear ends of chromosomes known as telomeres. Both genetic deletion and chemical inhibition of TRF1 have been shown to block the growth of lung carcinoma, glioblastoma, and renal cell carcinoma in mice without affecting mouse survival or tissue function, making TRF1 a potential therapeutic target in cancer(1-3). Here, we report the discovery of a series of fragment hits that bind at the interface between the TRFH domain of TRF1 (TRF1(TRFH)) and a peptide of TIN2 (TIN2(TBM)), an interaction essential for the recruitment of TRF1 to shelterin, using X-ray crystallography (XChem) and ligand-observed NMR (LO-NMR) fragment screening. We discovered a first-in-class inhibitor of the TRF1:TIN2 interaction (compound 40) that binds to TRF1(TRFH) with a K(D) of 29 microM (95% CI: 20-41 microM), displaces a TIN2 probe with an IC(50) of 67 microM (95% CI: 10-120 microM), and expels TRF1 from purified shelterin. Aided by a novel crystal system of TRF1(TRFH), we characterised fragments binding in a hotspot at the TRF1:TIN2 interface; these will serve as a starting point for the structure-guided development of potent inhibitors of TRF1 protein:protein interactions to disrupt shelterin complex assembly. Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening.,Casale G, Liu M, Le Bihan YV, Inian O, Stammers E, Caldwell J, van Montfort RLM, Collins I, Guettler S Sci Rep. 2025 Nov 20;15(1):40922. doi: 10.1038/s41598-025-23858-3. PMID:41266376[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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