Matrix metalloproteinases structure

Matrix metalloproteinase structural studies of the P -side inhibitors to date show a common set of inhibitor-enzyme interactions. This can be attributed primarily to the strong directional zinc-binding forces. Further stabilizing forces from the backbone hydrogen-bonding patterns common to a (3 sheet allow for minor adjustments due to the zinc interactions to be made while maintaining a common pharmacophore. 

Martin KH, Slack JK, Boerner SA et al (2002) Integrin connections map to infinity and beyond. Science 296 1652-1653 Massova I, Kotra LP, Fridman R et al (1998) Matrix metalloproteinases structures, evolution, and diversification. FASEB J 12 1075-1095... 

Matrix Metalloproteinases. Figure 2 ProMMP-2-TIMP-2 structure (adopted from [4]). TIMP-2 cartoon and transparent surface structure is shown in blue, MMP-2 in red. The C-terminal ends of both molecules are marked as spheres. 

Morgunova E, Tuuttila A, Bergmann U et al (2002) Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. Proc Natl Acad Sci USA 99 7414—7419... 

Fig. 3 The SAR by NMR approach. Example of a small bidentate molecule designed using this approach. The example shown is for the design of a potent inhibitors of the matrix metalloproteinase MMP3. (a) Docked structures of the identified fragment leads are shown with cyan carbons, whereas the linked compound is shown with green carbon atoms. All structures were experimentally determined by NMR. (b) Chemical structures (and in vitro potencies) of the fragment leads and subsequent high-affinity linked compounds. Adapted from [7]...

Morgunova E, Tuutila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, Tryggvason K. Structure of human pro-matrix metalloproteinase-2 activation mechanism revealed. Science 1999 284 1667-1670. 

Extended biological investigations concerning structure-function studies were further initiated to evaluate the abilities of these clusters to inhibit Con A-induced membrane type-1-matrix metalloproteinase (MTl-MMP)-mediated pro-MMP-2 activation, cell death, and antiproliferative property in mesenchymal stromal cells (MSC).83... 

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

To further extend the utility of structural methods, researchers compare solid state X-ray crystallographic and solution-state NMR structures to define important differences. For instance, the Bertini group has studied the enzyme matrix metalloproteinase 12 (MMP12), in the presence of its inhibitors. Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation, a fundamental step in tissue remodeling and repair. There are a great variety of enzymes of this type, the one studied here is one of many found in humans. Most MMPs have three domains (1) a prodomain that is removed... 

Figure 3.18 Secondary structure of matrix metalloproteinase 12 (MMP12) (A) PDB lYCM (structure determined using solution NMR) and (B) PDB IRMZ (structure determined using X-ray crystallography). Visualized using The PyMOL Molecular Graphics System and ChemDraw Ultra, version 10.0. (Printed with permission of Delano Scientific, LLC and CambridgeSoft Corporation.) (See color plate)...

Figure 3.18 Secondary structure of matrix metalloproteinase 12 (MMP12) (A) PDB lYCM (structure determined using solution NMR).

Matter, H., Schudok, M., Schwab, W., Thorwart, W., Barrier, D., Billen, G., Haase, B., Neises, B., Weithmann, K., WOLLMANN, T. Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10(11), 3529-3544. 

Terp, G.E., Cruciani, G., Christensen, I.T., and JORGENSEN, F.S. Structural differences of matrix metalloproteinases... 

Tetrahydroisoquinoline-3-carboxylate based matrix metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10, 3529-3544. 

Most applications of compounds of this class have been noted during the preceding discussion. The [6,5] fused heterocycle in compound 83 was introduced in one step using a Mitsunobu reaction (Equation 25). This compound, and a number of related structures, showed activity as inhibitors of matrix metalloproteinase <2003JME3840>. 

Structural Implications in the Design of Matrix-Metalloproteinase Inhibitors... 

Skiles JW, Gonnella NC, Jeng AY (2001) The design, structure, and therapeutic application of matrix metalloproteinase inhibitors. Curr Med Chem 8 425-474... 

DuPont s hybrid structure 19 [33] bears the signature of a dipeptide-based SAR on y-secretase and the reminiscent lead, which was synthesized in a matrix metalloproteinase (MMP) program. Removal of the central amide bond of the parent dipeptide, replacement of the hydroxamic acid by an amide, and introduction of a seven-membered lactam resulted in high activity and removed some of the problems associated with dipeptide lead structures. Hot labeling by photoactivation of I125-benzophenone specifically cross-linked the inhibitor to three cell-membrane proteins. 

Briknarova, K., Gehrmann, M., Banyai, L., Tordai, H., Patthy, L., and Llinas, M. (2001). Gelatin-binding region of human matrix metalloproteinase-2 Solution structure, dynamics, and function of the COL-23 two-domain construct. J. Biol. Chem. 276, 27613-27621. 

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