1JIZ

Crystal Structure Analysis of human Macrophage Elastase MMP-12

Summary for 1JIZ

• Entry DOI: 10.2210/pdb1jiz/pdb
• Descriptor: macrophage elastase MMP-12, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: matrix metalloproteinase, mmp-12, chronic obstructive pulmonary disease, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P39900
• Total number of polymer chains: 2
• Total formula weight: 38104.12

Authors

Nar, H.,Werle, K.,Bauer, M.M.T.,Dollinger, H.,Jung, B. (deposition date: 2001-07-03, release date: 2002-07-03, Last modification date: 2024-02-07)

Primary citation

Nar, H.,Werle, K.,Bauer, M.M.,Dollinger, H.,Jung, B.
Crystal structure of human macrophage elastase (MMP-12) in complex with a hydroxamic acid inhibitor.
J.Mol.Biol., 312:743-751, 2001

PubMed Abstract: Human macrophage elastase (MMP-12) is a member of the family of matrix metalloproteinases (MMPs) that plays, like other members of the family, an important role in inflammatory processes contributing to tissue remodelling and destruction. In particular, a prominent role of MMP-12 in the destruction of elastin in the lung alveolar wall and the pathogenesis of emphysema has been suggested. It is therefore an attractive therapeutic target. We describe here the crystal structure of the catalytic domain of MMP-12 in complex with a hydroxamic acid inhibitor, CGS27023A. MMP-12 adopts the typical MMP fold and binds a structural zinc ion and three calcium ions in addition to the catalytic zinc ion. The enzyme structure shows an ordered N terminus close to the active site that is identical in conformation with the superactivated form of MMP-8. The S1'-specificity pocket is large and extends into a channel through the protein, which puts MMP-12 into the class of MMPs 3, 8 and 13 with large and open specificity pockets. The two crystallographically independent molecules adopt different conformations of the S1'-loop and its neighbouring loop due to differing crystal packing environments, suggesting that flexibility or the possibility of structural adjustments of these loop segments are intrinsic features of the MMP-12 structure and probably a common feature for all MMPs. The inhibitor binds in a bidentate fashion to the catalytic zinc ion. Its polar groups form hydrogen bonds in a substrate-like manner with beta-strand sIV of the enzyme, while the hydrophobic substituents are either positioned on the protein surface and are solvent-exposed or fill the upper part of the specificity pocket. The present structure enables us to aid the design of potent and selective inhibitors for MMP-12.

PubMed: 11575929
DOI: 10.1006/jmbi.2001.4953

Experimental method

X-RAY DIFFRACTION (2.6 Å)