Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 A crystal structure

Area of Science:

• Biochemistry
• Structural Biology
• Pulmonary Medicine

Background:

• Macrophage elastase (MMP-12) is implicated in emphysema pathogenesis, primarily linked to cigarette smoking.
• MMP-12 contributes to lung damage by degrading elastin and inactivating alpha1-proteinase inhibitor (alpha1-PI).

Purpose of the Study:

• To determine the crystal structure of the human recombinant MMP-12 catalytic domain in complex with batimastat (BB-94).
• To elucidate the structural basis for MMP-12's substrate specificity and its role in emphysema.

Main Methods:

• X-ray crystallography was used to determine the structure of the MMP-12-batimastat complex.
• Data was collected to 1.1 Å resolution and refined to an R-value of 0.165.

Main Results:

• The MMP-12 structure exhibits an overall fold similar to other MMPs but with distinct features in its active-site cleft.
• Unique characteristics include an S-shaped double loop, a planar S2-site, and a continuous S1'-subsite, potentially allowing binding of Arg residues.
• The active site is well-suited for cleaving the alpha1-PI sequence, and shares substrate similarities with MMP-7.

Conclusions:

• The determined MMP-12 structure provides a template for designing specific emphysema therapeutics.
• Further studies using this structure can clarify MMP-12's role in disease through mutant construction.