9HFH

Crystal structure of human TRF1 TRFH domain in complex with compound 16

This is a non-PDB format compatible entry.

Summary for 9HFH

• Entry DOI: 10.2210/pdb9hfh/pdb
• Descriptor: Telomeric repeat-binding factor 1, 5-cyclobutyl-3-pyridin-2-yl-1,2,4-oxadiazole, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: telomere, shelterin, inhibitor, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 26114.76

Authors

Casale, G.,Le Bihan, Y.-V.,van Montfort, R.L.M.,Guettler, S. (deposition date: 2024-11-15, release date: 2025-11-26, Last modification date: 2025-12-03)

Primary citation

Casale, G.,Liu, M.,Le Bihan, Y.V.,Inian, O.,Stammers, E.,Caldwell, J.,van Montfort, R.L.M.,Collins, I.,Guettler, S.
Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening.
Sci Rep, 15:40922-40922, 2025

PubMed Abstract: TRF1 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. Here, we report the discovery of a series of fragment hits that bind at the interface between the TRFH domain of TRF1 (TRF1) and a peptide of TIN2 (TIN2), 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 with a K of 29 µM (95% CI: 20-41 µM), displaces a TIN2 probe with an IC of 67 µM (95% CI: 10-120 µM), and expels TRF1 from purified shelterin. Aided by a novel crystal system of TRF1, 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.

PubMed: 41266376
DOI: 10.1038/s41598-025-23858-3

Experimental method

X-RAY DIFFRACTION (2.12 Å)