The human TIMP-1 unbound structure provides a platform for fragment screening.

Area of Science:

• Structural biology
• Biochemistry

Background:

• Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates extracellular matrix remodeling and remyelination.
• TIMP-1 is a therapeutic target in cancer due to its role in tumorigenic signaling.
• No unbound structure of TIMP-1 was previously available.

Purpose of the Study:

• To determine the first unbound crystal structure of human TIMP-1.
• To provide a structural basis for the discovery of TIMP-1 ligands.

Main Methods:

• X-ray crystallography at 1.95 Å resolution.
• Structure comparison with MMP-bound TIMP-1 complexes.
• Crystallization optimization using additive screens.

Main Results:

• The first high-resolution unbound crystal structure of human TIMP-1 was determined.
• The unbound structure exhibits localized conformational changes and altered hydrogen bonding compared to MMP-bound forms.
• The structure indicates increased structural plasticity in unbound TIMP-1.
• The crystal form is suitable for drug screening.

Conclusions:

• The determined unbound TIMP-1 structure offers insights into its conformational flexibility.
• This structure serves as a foundation for structure-based drug discovery targeting TIMP-1.
• Potential therapeutic applications include cancer and demyelinating disorders like multiple sclerosis.