2poj
|
NMR Solution Structure of the Inhibitor-Free State of Macrophage Metalloelastase (MMP-12)
OverviewOverview
Macrophage metalloelastase or matrix metalloproteinase-12 (MMP-12) appears, to exacerbate atherosclerosis, emphysema, aortic aneurysm, rheumatoid, arthritis, and inflammatory bowel disease. An inactivating E219A mutation, validated by crystallography and NMR spectra, prevents autolysis of MMP-12, and allows us to determine its NMR structure without an inhibitor. The, structural ensemble of the catalytic domain without an inhibitor is based, on 2813 nuclear Overhauser effects (NOEs) and has an average RMSD to the, mean structure of 0.25 A for the backbone and 0.61 A for all heavy atoms, for residues Trp109-Gly263. Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly more deeply recessed under, the beta-sheet. This opens a pocket between hB and beta-strand IV in the, active-site cleft. Both hB and an internal cavity are shifted toward, beta-strand I, beta-strand III, and helix A on the back side of the, protease. About 25 internal NOE contacts distinguish the inhibitor-free, solution structure and indicate hB's greater depth and proximity to the, sheet and helix A. Line broadening and multiplicity of amide proton NMR, peaks from hB are consistent with hB undergoing a slow conformational, exchange among subtly different environments. Inhibitor-binding-induced, perturbations of the NMR spectra of MMP-1 and MMP-3 map to similar, locations across MMP-12 and encompass the internal conformational, adjustments. Evolutionary trace analysis suggests a functionally important, network of residues that encompasses most of the locations adjusting in, conformation, including 18 residues with NOE contacts unique to, inhibitor-free MMP-12. The conformational change, sequence analysis, and, inhibitor perturbations of NMR spectra agree on the network they identify, between structural scaffold and the active site of MMPs.
About this StructureAbout this Structure
2POJ is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Macrophage elastase, with EC number 3.4.24.65 Full crystallographic information is available from OCA.
ReferenceReference
Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment., Bhaskaran R, Palmier MO, Bagegni NA, Liang X, Van Doren SR, J Mol Biol. 2007 Dec 14;374(5):1333-44. Epub 2007 Oct 16. PMID:17997411
Page seeded by OCA on Wed Jan 23 11:51:56 2008