Again, the Cys29 (green) at the catalytic site is blocked by the activation segment passing through the cleft between the domains - this time, twice.

The final example is procathepsin K, which has been implicated in bone resorption processes. In this enzyme, the activation segment is the first 99 residues, which again slot into the catalytic site, especially Lsy74 - Pro81:

Procathepsin K, Activation Segment	Procathepsin K, Active Site (1by8)
Procathepsin K, Secondary Structure

• Cleavage of the activation segment is initiated at pH 4 (conformational change?)

• One procathepsin hydrolyzes its own activation segment, in pieces

• That activated cathepsin then attacks other procathepsins

The malaria parasite, Plasmodium falciparum, uses cysteine proteases to hydrolyze hemoglobin to obtain free amino acids essential to its survival.

• Its genome encodes 33 cysteine proteases

• Four of these are papain-like, and are known as falcipains

• Not surprisingly, these are targets of drug development

P. falciparum Falcipain 2 (2ghu)	The Catalytic Site
Superposition of Papain and Falcipain 2 (rmsd = 2.04 A)	Falcipain 2 with Experimental Drug Bound (3bpf)
Mode of Action of Experimental Drug

Another parasite, Trypanosoma cruzi, likewise expresses a cysteine protease, called cruzain or cruzipain, which is essential for its life cycle and for its interaction with host cells. Many of those infected with the parasite develop the fatal condition known as Chagas' disease.

• Many species that express cysteine proteases, including the parasites, also express inhibitors, known as cystatins, for those proteases.

• Again, the protease is the target of drug development.

Chagasin, the cystatin from T. cruzi (2h7w)	Cruzain with Experimental Drug Bound (1ewl)