292
H. TscHEscHE and M. FARR
l
Fig. 21.2. Structure of the catalytic domain of MMP-S (Bode et al. 1994, Reinemer et aJ. 1994). Left
side: cdMMP_SPhe79; right side: cdMMP_SMet80 (The arrow indicates that the N-terminalless ordered
amino acids are not localized in the X-ray structure analysis.)
as an active enzyme (Pei and Weiss 1995). Because the membrane-type MMPs
possess a potential fur in recognition site too (Fig. 21.1), they might also be activated within cells (Sato et al. 1996b). On the other hand activation of progelatinase A (MMP-2) on cell surfaces is catalyzed by the membrane-type MMPs,
which are anchored in the cell membrane by a hydrophobic, C-terminal transmembrane domain (Fig. 21.1). This activation process is mediated by TIMP-2,
that binds N-terminally to one molecule MT-MMP and captures C-terminally the
progelatinase and presents it to an adjacent active molecule of MT-MMP for activation (Sato et al. 1996a). Other domains of MMPs like the hemopexin like
domain and the fibronectin like domain of gelatinases determine individual substrate specificities. For example, the hemopexin like domain of the collagenases
is essential for their tripelhelicase activity towards native collagen type I, II and
III (Schnierer et al. 1993).
3
Biomolecular Interaction with liMPs
The physiological antagonists of the matrix metalloproteinases are the tissue
inhibitors of metalloproteinases (TIMPs) comprising at least four proteins. The
primary structure of their 184 to 195 amino acids polypeptide chain is dominated by twelve highly conserved cysteine residues which form six disulfide
bonded loops (Williamson et al. 1990).
The MMP inhibitory activity ofTIMPs is located to the three N-terminalloops
(DeClerck et al. 1993, Murphy et al. 1991, O'Shea et al. 1992, Williamson et al.
1996), while the C-terminalloops include additional binding sites for the gelatinases outside their catalytic domain (Huang et al. 1996, Murphy et al. 1991, Willenbrock et al. 1993). Because of these two major domains there are several binding modes comprising binary complexes like (pro)gelatinase B/TIMP-1 (Wilhelm
H. TscHEscHE and M. FARR
l
Fig. 21.2. Structure of the catalytic domain of MMP-S (Bode et al. 1994, Reinemer et aJ. 1994). Left
side: cdMMP_SPhe79; right side: cdMMP_SMet80 (The arrow indicates that the N-terminalless ordered
amino acids are not localized in the X-ray structure analysis.)
as an active enzyme (Pei and Weiss 1995). Because the membrane-type MMPs
possess a potential fur in recognition site too (Fig. 21.1), they might also be activated within cells (Sato et al. 1996b). On the other hand activation of progelatinase A (MMP-2) on cell surfaces is catalyzed by the membrane-type MMPs,
which are anchored in the cell membrane by a hydrophobic, C-terminal transmembrane domain (Fig. 21.1). This activation process is mediated by TIMP-2,
that binds N-terminally to one molecule MT-MMP and captures C-terminally the
progelatinase and presents it to an adjacent active molecule of MT-MMP for activation (Sato et al. 1996a). Other domains of MMPs like the hemopexin like
domain and the fibronectin like domain of gelatinases determine individual substrate specificities. For example, the hemopexin like domain of the collagenases
is essential for their tripelhelicase activity towards native collagen type I, II and
III (Schnierer et al. 1993).
3
Biomolecular Interaction with liMPs
The physiological antagonists of the matrix metalloproteinases are the tissue
inhibitors of metalloproteinases (TIMPs) comprising at least four proteins. The
primary structure of their 184 to 195 amino acids polypeptide chain is dominated by twelve highly conserved cysteine residues which form six disulfide
bonded loops (Williamson et al. 1990).
The MMP inhibitory activity ofTIMPs is located to the three N-terminalloops
(DeClerck et al. 1993, Murphy et al. 1991, O'Shea et al. 1992, Williamson et al.
1996), while the C-terminalloops include additional binding sites for the gelatinases outside their catalytic domain (Huang et al. 1996, Murphy et al. 1991, Willenbrock et al. 1993). Because of these two major domains there are several binding modes comprising binary complexes like (pro)gelatinase B/TIMP-1 (Wilhelm