Matrilysin-inhibitor complexes: common themes among metalloproteases.
ABSTRACT Matrix metalloproteases are a family of enzymes that play critical roles in the physiological and pathological degradation of the extracellular matrix. These enzymes may be important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis. Matrilysin is the smallest member of this family of enzymes, all of which require zinc for catalytic activity. The first X-ray crystal structures of human matrilysin are presented. Inhibitors of metalloproteases are often characterized by the chemical group that interacts with the active site zinc of the protein. The structures of matrilysin complexed with hydroxamate (maximum resolution 1.9 A), carboxylate (maximum resolution 2.4 A), and sulfodiimine (maximum resolution 2.3 A) inhibitors are presented here and provide detailed information about how each functional group interacts with the catalytic zinc. Only the zinc-coordination group is variable in this series of inhibitors. Examination of these inhibitor-matrilysin complexes emphasizes the dominant role the zinc-coordinating group plays in determining the relative potencies of the inhibitors. The structures of these matrilysin-inhibitor complexes also provide a basis for comparing the catalytic mechanism of MMPs and other metalloproteins.
- SourceAvailable from: Mina M Benjamin
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- "MMPs may function through one of three catalytic mechanisms. The first mechanism called the base-catalysis mechanism is carried out by the conserved glutamate residue and Zn 2+ (Browner et al., 1995). In the second mechanism, the catalytic action involves an interaction between a water molecule and Zn 2+ during the acid-base catalysis (Kester and Matthews, 1977). "
ABSTRACT: Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolytic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune disease, and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only one MMP inhibitor, i.e., doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.EXS 01/2012; 103:209-79. DOI:10.1007/978-3-0348-0364-9_7
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- "This superfamily of proteases is defined by the presence of a Zn 2? ion at the catalytic center, which is coordinated by three histidine residues in the zinc-binding consensus sequence HExxHxxGxxH that is present in all proteolytically active metzincins, and a characteristic, strictly conserved methionine-containing tight 1,4 beta turn forming a hydrophobic cleft for the catalytic zinc ion (Bode et al. 1993). Catalysis of protein substrates is (most probably) carried out via a general base mechanism involving activation of a zinc-bound water molecule by the carboxylate group of the conserved glutamate residue in the catalytic pocket followed by attack of water on the polarized carbonyl group in the substrate's scissile bond (Browner et al. 1995). "
ABSTRACT: Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn(2+) ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the 'MMP nomenclature' and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction.Amino Acids 07/2011; 41(2):271-90. DOI:10.1007/s00726-010-0689-x · 3.65 Impact Factor
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- "This is achieved through an induced fit mechanism where the Arg 214 residue is displaced by inhibitor 4, creating a larger, more accommodating substrate pocket, illustrating the importance of protein dynamics . While MMP-7 also exhibits a smaller pocket due to occlusion by the analogous Tyr 214 , an induced fit conformational change has not been observed for MMP-7 due to its shorter specificity loop creating a more rigid S1' pocket  . Intermediate S1' pockets are observed in MMP-8 as well as in the gelatinases MMP-2 and -9. "
ABSTRACT: This short review highlights some recent advances in matrix metalloproteinase inhibitor (MMPi) design and development. Three distinct approaches to improved MMP inhibition are discussed: (1) the identification and investigation of novel zinc-binding groups (ZBGs), (2) the study of non-zinc-binding MMPi, and (3) mechanism-based MMPi that form covalent adducts with the protein. Each of these strategies is discussed and their respective advantages and remaining challenges are highlighted. The studies discussed here bode well for the development of ever more selective, potent, and well-tolerated MMPi for treating several important disease pathologies.Biochimica et Biophysica Acta 09/2009; 1803(1):72-94. DOI:10.1016/j.bbamcr.2009.08.006 · 4.66 Impact Factor