Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

Matrix Metalloproteinases: A Review

The atomic structure of protein-protein recognition sites.

Radical-mediated damage to proteins may be initiated by electron leakage, metal-ion-dependent reactions and autoxidation of lipids and sugars. The consequent protein oxidation is O2-dependent, and involves several propagating radicals, notably alkoxyl radicals. Its products include several categories of reactive species, and a range of stable products whose chemistry is currently being elucidated. Among the reactive products, protein hydroperoxides can generate further radical fluxes on reaction with transition-metal ions; protein-bound reductants (notably dopa) can reduce transition-metal ions and thereby facilitate their reaction with hydroperoxides; and aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some of the reactive species, e.g. by reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. Thus cells can generally remove oxidized proteins by proteolysis. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, this may contribute to the observed accumulation and damaging actions of oxidized proteins during aging and in pathologies such as diabetes, atherosclerosis and neurodegenerative diseases. Protein oxidation may also sometimes play controlling roles in cellular remodelling and cell growth. Proteins are also key targets in defensive cytolysis and in inflammatory self-damage. The possibility of selective protection against protein oxidation (antioxidation) is raised.

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Biochemistry and pathology of radical-mediated protein oxidation

https://structbio.vanderbilt.edu/comp/workshops/rosetta_11/gray_2003_jmolbio_proteindock.pdf

Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations.

Publisher Summary This chapter summarizes the experimental information on protein energetics. This field is developing fast and the concept of the energetics of protein structure has changed considerably during the past few years based on new findings. The proteins which are presented in the chapter are selected from a large number of proteins for which the thermodynamics of unfolding are studied in laboratory. The analysis of protein energetics presented in this chapter is based on several assumptions: (1) protein groups contribute additively, and proportionally as their surfaces, to the overall thermodynamic effects of unfolding; (2) the protein interior closely resembles an organic crystal in the way groups are packed and the energetics of the interactions among these groups are similar to those in the organic crystals; and (3) under certain conditions the denatured protein can be regarded as unfolded. The main criteria in choosing these proteins have been the reversibility of the denaturation process modeling unfolding, the completeness of this unfolding, the reliability of thermodynamic data on this process, and the resolution of the three dimensional structure of the given protein. The latter is important to investigate the correlation between thermodynamic and structural characteristics of protein, including the water-ASA of various groups in the native and unfolded states, the number of hydrogen bonds, and the extent of van der Waals contacts in the native state.

Energetics of protein structure.

An exceptionally stable 1:2 complex [FeL2]3− is formed from the ligand H3L and FeIII. In contrast, the affinity of this ligand for other biometals is relatively small. These properties make H3L a highly promising candidate for medical applications (e.g. for the treatment of iron overload).

4-3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl-benzoic acid : a novel efficient and selective iron(iii) complexing agent

Crystal and molecular structure of the bovine α-chymotrypsin-eglin c complex at 2.0 Å resolution

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2885%2980873-5

Crystal and molecular structure of the inhibitor eglin from leeches in complex with subtilisin Carlsberg.

Isolation and characterization of an enkephalin-degrading aminopeptidase from rat brain.

Man is unable to actively eliminate iron from the body, once it has been acquired. Toxic and eventually lethal levels of iron accumulate as a result of repeated transfusions, e.g. in s-thalassemia major, or due to excessive dietary iron uptake in anemias and hereditary hemochromatosis. Excess iron is deposited in the form of hemosiderins (insoluble “iron cores” of ferritin) mainly in the liver, spleen, many endocrine organs and in the myocardium. The exact mechanism of iron damage to these tissues is unknown, but it is established that organ failure correlates with iron burden in these tissues. Except for infectious diseases, cardiac complications are the major cause of death in s-thalassemia major patients.

Hans Peter Schnebli

Papers

4-3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl-benzoic acid : a novel efficient and selective iron(iii) complexing agent

Crystal and molecular structure of the bovine α-chymotrypsin-eglin c complex at 2.0 Å resolution

Crystal and molecular structure of the inhibitor eglin from leeches in complex with subtilisin Carlsberg.

Isolation and characterization of an enkephalin-degrading aminopeptidase from rat brain.

ICL670A: preclinical profile.