Thermolysin catalytic domain

An 80- to 90-residue N-terminal propeptide domain contains a cysteine whose -S group binds to the active site zinc, screening it from potential substrates. The central catalytic domain is followed by a hinge region and a C-terminal domain that resembles the serum iron binding and transporting hemopexin.427/436 The mechanism of action is probably similar to that of thermolysin.430... 

Figure 14.2 Superposed X-ray structures of the catalytic domains of UA4H (blue), angiotensin-converting enzyme (red), and thermolysin (yellow), each with bound zinc ion (colored accordingly).

Gluzincins are proteins with the consensus HexxH( > 20)E, where the third zinc ligand, a glutamate, lies at least 20 residues C-terminal to the zincin motif (Table 2). The archetypical protein of this class, thermolysin consists of two domains, with the active site located between the N-terminal catalytic domain and the all alpha C-terminal domain (Fig. 7). With the limited data available, a comparison of topological matches of the observed structures with their cor-... 

Figure 8. Superposition of the N-terminal domain of thermolysin (silver) and the catalytic domain of collagenase (orange). Stereo ribbon diagram illustrating the common topology between representative structures of the long spacer (silver) and short spacer (orange) families defining the zinc-endoprotease fold.

Figure 7. The structure of thermolysin. Ribbon representation of the structure of thermolysin (silver, Brookhaven Databank [53] code 3TLN) shown with a bound inhibitor (green). The catalytic zinc atom (cyan) and structural calcium atoms (magenta) are shown. The active site is located between the N-terminal zinc protease domain and the alpha helical C-terminal domain. Zinc binding residues are in blue and the residue assisting catalysis is shown in red.

In the C-terminal domain are five helices in a closed bundle. This characteristic fold is typical of thermolysin-like peptidases. Clan MC contains metallocarbox-ypeptidases which belong to only one family (M14) which is divided into the subfamilies A, B and C. Typical for this clan is that one zinc ion is tetrahedrally coordinated by a water molecule, two histidine and one glutamate residues. Clan MF includes aminopeptidases that require cocatalytic zinc ions for their enzymatic activity. The well-known leucyl aminopeptidase has a two-domain structure bearing the active site in the C-terminal domain. Whereas exopeptidases of clan MG require cocatalytic ions of cobalt or manganese, clan MH contains the third group of metallopeptidases that also require cocatalytic metal ions, but here these are all zinc ions. The third clan in which cocatalytic metal ions are necessary is clan MF with zinc or manganese. Only one catalytic zinc ion is required for peptidases of clans MA, MB, MC, MD and ME. 

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