crystal structures of tbcatb and rhodesain, potential chemotherapeutic targets and major cysteine proteases of trypanosoma brucei晶体结构tbcatb rhodesain,潜在的化学疗法的目标和主要的半胱氨酸蛋白酶的锥虫属brucei.pdfVIP

Crystal Structures of TbCatB and Rhodesain, Potential Chemotherapeutic Targets and Major Cysteine Proteases of Trypanosoma brucei 1. 1.¤ 1 2 1 Iain D. Kerr , Peng Wu , Rachael Marion-Tsukamaki , Zachary B. Mackey , Linda S. Brinen * 1 Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Pathology and the Sandler Center for Basic Research in Parasitic Diseases, University of California San Francisco, San Francisco, California, United States of America Abstract Background: Trypanosoma brucei is the etiological agent of Human African Trypanosomiasis, an endemic parasitic disease of sub-Saharan Africa. TbCatB and rhodesain are the sole Clan CA papain-like cysteine proteases produced by the parasite during infection of the mammalian host and are implicated in the progression of disease. Of considerable interest is the exploration of these two enzymes as targets for cysteine protease inhibitors that are effective against T. brucei. Methods and Findings: We have determined, by X-ray crystallography, the first reported structure of TbCatB in complex with the cathepsin B selective inhibitor CA074. In addition we report the structure of rhodesain in complex with the vinyl- sulfone K11002. Conclusions: The mature domain of our TbCatNCA074 structure contains unique features for a cathepsin B-like enzyme including an elongated N-terminus extending 16 residues past the predicted maturation cleavage site. N-terminal Edman sequencing reveals an even longer extension than is observed amongst the ordered portions of th