Zinc endoproteases

Matrix Metalloproteases. Matrix metal-loproteases (MMPs) are a large and diverse family of zinc endoproteases. Several members of this family (such as the collagenases and the stromelysins) are thought to have important roles in proliferative diseases, including arthritis, retinopathy, and metastatic in-... 

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 9. Thermolysin-inhibitor complex - an example of inhibitors bound to zinc endoproteases with the long spacer consensus. A stereo view of the active site site of thermolysin showing details of enzyme-inhibitor 2 interactions (Brookhaven Databank Code 5TLN). Enzyme side chains involved in inhibitor recognition are shown in magenta. The color code is as given for Fig. 6.

An important feature of long spacer zinc-endoproteases like thermolysin, as revealed by comparisons of the free enzyme and that complexed with inhibitors [40,41] is that conformational change is an essential component for catalytic activity. A similar conformational change is also probable [15,18,26] for the short spacer family, although a definite confirmation must await more structural information on equivalent free and inhibited proteins of this class. 

In contrast, for inhibitors interacting with members of short consensus zinc endoprotease family, like the matrixins [17,19-23,25], the subsites P2 and P3 are suitably orientated for bridging. Molecules having the essential zinc-binding functionality and macrolactams span-... 

Figure 11. Cyclic inhibitors 3 and 4 of zinc-endoproteases. The differences in the conformation of the inhibitors leads to separate series of inhibitors for the two families. For details, see text.

Figure 14. Zinc endoproteases a structural superfamily. The central panel shows the superposition of the alpha carbon atoms of the topologically equivalent catalytic domains of proteins from the long consensus family (silver) and the short spacer family (orange). Various consensus sequences are given (see text) with the zinc-chelating residues shown in white. Full blue arrows indicate presence of motif in observed three-dimensional structures corresponding to the zinc endoprotease fold shown in the central panel. Dotted lines indicate putative structure-sequence relationships discussed in the text.

The growing family of known divalent cation-dependent proteases such as insulinase [51] and dibasic convertase [52], with the variant consensus HxxeH, also present interesting questions as to the possibility of a mirrored active site with or without conservation of the overall topology. Conversely, it is possible that entirely different proteins which have no zinc dependency and completely separate function may adopt the zinc endoprotease topology, simply because this fold provides a stable modular scaffold useful in the construction of multidomain proteins. Results of further structural studies are eagerly awaited. 

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