The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas' disease. It is functionally involved in host cell invasion. We have determined the three-dimensional crystal structure of TcMIP at 1.7 Å resolution. The monomeric protein displays a peptidyl-prolyl cis-trans isomerase (PPlase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted β-sheet of the core is extended by an extra β-strand, preceded by a long, exposed N-terminal α-helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N-terminal α-helix, can substitute for TcMIP. An additional exposed α-helix, this one unique to TcMIP, is located in the C-terminus of the protein. The high-resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis.This work was supported by grants from Ministerio de Educación y Cultura (PB98-1631 and 2FD97-0518), CSIC and Generalitat de Catalunya (CERBA and 1999SGR188) to M.C., grant PB98-0479 to A.G. and by grant BIO2000-1659 to F.X.G.-R. P.J.B.P. and S.M.-R. acknowledge postdoctoral fellowships from FCT (Portugal). Data collection at DESY was supported by EC grants ERBFMGECT980134 and HPRI-CT-1999-00017 to EMBL-HamburgPeer Reviewe
