The crystal structure of the Leishmania major surface proteinase leishmanolysin (gp63).
BACKGROUND
Despite their medical importance, there is little available structural information for the surface antigens of infectious protozoa. Diseases caused by the protozoan parasite Leishmania are common in many developing countries. Human infection occurs during the bite of infected sandfilies, when Leishmania promastigote cells from the insect gut enter the bloodstream. Promastigotes in the blood parasitize macrophages, often causing serious disease. Leishmanolysin is the predominant protein surface antigen of promastigotes, and is assumed to have a key role during infection. Leishmanolysin is a membrane-bound zinc proteinase, active in situ. Similar molecules exist in other trypanomastid protozoa.


RESULTS
Two crystal forms of leishmanolysin were obtained from protein purified from promastigote membranes. A single lead derivative in both crystal forms was used to solve the structure. The structure reveals three domains, two of which have novel folds. The N-terminal domain has a similar structure to the catalytic modules of zinc proteinases. The structure clearly shows that leishmanolysin is a member of the metzincin class of zinc proteinases.


CONCLUSIONS
The unexpected metzincin features of the leishmanolysin structure suggest that the metzincin fold may be more widespread than indicated by sequence homologies amongst existing metzincin zinc proteinases. The similarity of the active-site structure to previously well characterized metzincin class zinc proteinases should aid the development of specific inhibitors. These inhibitors might be used to determine the function of leishmanolysin in the insect and during mammalian infection, and may aid the development of drugs for human leishmaniasis.
Schlagenhauf
E
E
EMBL Heidelberg, Biological Structures and Biocomputing Programme, Germany.
Etges
R
R
Metcalf
P
P
D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000737:chemistry; D001665:Binding Sites / Q000502:physiology; D018320:Leishmania major / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000737:chemistry
D000953:Antigens, Protozoan; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania; D015032:Zinc