The first unbound crystal structure of human TIMP-1 was resolved at 1.95 Å resolution, revealing localized conformational changes and providing a platform for fragment screening.
The first unbound crystal structure of human TIMP-1 provides a robust structural basis for the discovery of TIMP-1 ligands with clinical potential.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a critical regulator of extracellular matrix remodelling and an important mediator of remyelination in demyelinating disorders such as multiple sclerosis. In addition, TIMP-1 has emerged as a promising therapeutic target in cancer due to its interaction with CD63, which promotes tumorigenic signalling and carcinogenesis. Although several structures of TIMP-1 bound to matrix metalloproteinases have been reported, no unbound structure with all druggable sites available has previously been reported. Here, we present the first unbound crystal structure of human TIMP-1, resolved at 1.95 Å resolution. Comparison with the MMP-bound complex reveals localized conformational changes and altered intramolecular hydrogen bonding in the unbound structure, indicating increased structural plasticity in the absence of the protease. Crystals were obtained in multiple conditions, but only two diffracted to high resolution. Although optimization and seeding did not significantly improve the morphology, the additive screen enhanced both the morphology and reproducibility and provided intrinsic cryoprotection. The resulting crystal form proved compatible with soaking-based screening campaigns, providing a robust structural basis for the discovery of TIMP-1 ligands with clinical potential.
Shemy et al. (2026) studied this question. The first unbound crystal structure of human TIMP-1 was resolved at 1.95 Å resolution, revealing localized conformational changes and providing a platform for fragment screening.