Stromelysin inhibition

Three-Dimensional Structure of the Inhibited Catalytic Domain of Human Stromelysin-1 by Heteronuclear NMR Spectroscopy... 

III. ASSIGNMENT OF THE RESONANCES OF THE INHIBITED CATALYTIC DOMAIN OF STROMELYSIN-1... 

For the complex of the inhibited catalytic domain of stromelysin-1, 2-D doubly filtered COSY and TOCSY experiments performed... 

An advantage of NMR spectroscopy is the analysis of protein dynamics. Measurement and analysis of the relaxation parameters R1 R2, and the 15N NOE of 15N-labeled proteins leads to an order parameter (S2) that can describe the relative mobility of the backbone of the protein. Both collagenase-1 and stromelysin-1 have been studied either as inhibited complexes or the free protein [19, 52], Stromleysin-1 was studied with inhibitors binding to prime or nonprime subsites. Presence or absence of inhibitors in the nonprime sites had minor effects on the highly ordered structure of residues in these subsites, which are in contact with the... 

Gooley PR, O Connell JF, Marcy AI, Cuca GC, Salowe SP, Bush BL, Hermes JD, Hagmann WK, Esser CK, Springer JP, Johnson BA. The NMR structure of the inhibited catalytic domain of human stromelysin-1. Nat Struct Biol 1994 1 111-118. 

Becker JW, Marcy AI, Rokosz LL, Axel MG, Burbaum JJ, Fitzgerald PMD, Cameron PM, Esser CK, Hagmann WK, Hermes JD, Springer JP. Stromelysin-1 Three-dimensional structure of the inhibited catalytic domain and of the C-truncated proenzyme. Prot Sci 1995 4 1966-1976. 

Inhibitors of human neutrophil collagenase and human stromelysin have been designed (577) which are based on previous classes of MMP inhibitors, iV-carboxyalkyl peptides (578, 579), and peptide-based hy-droxamic acids (117) (580, 581). The -CH3 and 2-phenylethyl groups are important for inhibition of MMP-3. The X-ray crystal structure of MMP-3 with bound 117 shows that the inhibitor chelates Zn(II)... 

Hui A, Min WX, Tang J, Cruz TE Inhibition of activator protein I activity by paclitaxel suppresses interleukin-1 -induced colla-genase and stromelysin expression by bovine chondrocytes. Arthritis Rheum 1998 4l(5) 869-876. 

Shen, A. Colletti, P. A. Krieter, W. K. Hagmann, Inhibition of stromelysin-1 (MMP-3) by Pl -biphenylylethyl carbox-yalkyldipeptides,/. Med. Chem. 1997,... 

Mechanistically, inhibition must not necessarily block the active site itself, but it can exert allosteric effects on the substrate-binding pocket, which thereby enhances or suppresses enzymatic activity. Additional considerations regarding enzymatic reactions are discussed in Reference 86. SAR by NMR has been successfully applied to various systems [i.e., for disrupting intracellular protein-protein binding (87) as well as cytokine-receptor interaction (88)]. High-affinity enzyme inhibitors have been developed by this technique [e.g., for the metalloproteinase Stromelysin (89) and the protein tyrosine phosphatase IB (90)]. 

Research on the therapeutic use of MMP inhibitors for the treatment of cancers has shown promise [80]. Of particular interest has been data showing that MMP-3 (also called stromelysin-1) plays an important role in the promotion of neoplasia in mice and that inhibition of MMP-3 blocked this activity [80],... 

Drug Discovery Strategies and Methods, ed. A. Makriyannis and D. Biegel, Marcel Dekker, Inc., New York, N.Y., 2004 R 186 P.R. Gooley, Three-Dimensional Structure of the Inhibited Catalytic Domain of Human Stromelysin-1 by Heteronuclear NMR Spectroscopy , p. 61... 

---