Crystal structure of chagasin, the endogenous cysteine-protease inhibitor from Trypanosoma cruzi.
Trypanosoma cruzi chagasin belongs to a recently discovered family of cysteine protease inhibitors found in lower eukaryotes and prokaryotes but not in mammals. Chagasin binds tightly to cruzain, the major lysosomal T. cruzi cysteine protease, involved with infectivity and survival of the parasite in mammalian host cells. In the scope of a project to characterize proteins diferentially expressed during T. cruzi metacyclogenesis, we have determined the crystal structure of chagasin, which is now the first X-ray structure of a chagasin-like cysteine protease inhibitor to be reported. The structure was solved by the SIRAS method and refined at 1.7A resolution and a comparison with the two NMR structures available revealed some differences in the loops involved in binding to cysteine proteases. The highly flexible loop 4 could be entirely modeled and residues 29-33 from loop 2 form a 3(10)-helix structure that may be important to stabilize the loop conformation. Chagasin crystal structure was docked to the highest resolution structure available of cruzain and a model of chagasin-cruzain interaction was analyzed. The knowledge of the chagasin crystal structure may contribute to the elucidation of the molecular mechanism involved in the inhibition of cruzain and other T. cruzi cysteine proteases.
Figueiredo da Silva
Aline Almeida
AA
Centro de Biologia Molecular Estrutural, Laboratório Nacional de Luz Síncrotron, LNLS, P.O. Box 6192, CEP 13084-971, Campinas SP, Brazil.
de Carvalho Vieira
Leandro
L
Krieger
Marco Aurélio
MA
Goldenberg
Samuel
S
Zanchin
Nilson Ivo Tonin
NI
Guimarães
Beatriz Gomes
BG
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014349:Trypanosoma cruzi
D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; C435145:chagasin, Trypanosoma; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi