Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Matrix metalloproteinases (MMPs) are crucial enzymes involved in extracellular matrix remodeling.
• Human matrix metalloproteinase-9 (MMP9) plays significant roles in physiological and pathological processes.
• Understanding the structural basis of MMP9 is essential for developing targeted therapeutics.

Purpose of the Study:

• To determine the X-ray crystal structure of the proform of human MMP9.
• To compare the structural features of MMP9 with its close homolog, MMP2.
• To identify potential targets for the design of MMP9-specific inhibitors.

Main Methods:

• X-ray crystallography was used to solve the structure of the MMP9 proform to 2.5 A resolution.
• The structure included the prodomain, catalytic domain, and three fibronectin type II (FnII) domains.
• Comparative structural analysis was performed with the known structure of MMP2.

Main Results:

• The prodomain of MMP9 occupies the active-site cleft, inhibiting catalytic activity.
• Key active-site residues and the cysteine-switch peptide show high conservation between MMP9 and MMP2.
• The S1' inhibitor-binding pocket in MMP9 is large, similar to MMP2, but a subtle difference at residue 424 (Arg in MMP9, Thr in MMP2) may offer a design opportunity.
• The second FnII domain in MMP9 does not interact with the catalytic domain, unlike in MMP2.

Conclusions:

• The structural similarity between MMP9 and MMP2 presents a challenge for developing specific inhibitors.
• A minor difference in the S1' pocket, specifically the orientation of Arg424, could be exploited for inhibitor design.
• The distinct interaction of the second FnII domain in MMP9 compared to MMP2 warrants further investigation.