3F75

Activated Toxoplasma gondii cathepsin L (TgCPL) in complex with its propeptide

Summary for 3F75

• Entry DOI: 10.2210/pdb3f75/pdb
• Descriptor: Cathepsin L Protease, Cathepsin L Propeptide, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: medical structural genomics of pathogenic protozoa, msgpp, cysteine protease, parasite, protozoa, hydrolase, thiol protease
• Biological source: Toxoplasma gondii; More
• Total number of polymer chains: 2
• Total formula weight: 37435.75

Authors

Larson, E.T.,Merritt, E.A.,Medical Structural Genomics of Pathogenic Protozoa (MSGPP) (deposition date: 2008-11-07, release date: 2008-11-25, Last modification date: 2024-10-30)

Primary citation

Larson, E.T.,Parussini, F.,Huynh, M.H.,Giebel, J.D.,Kelley, A.M.,Zhang, L.,Bogyo, M.,Merritt, E.A.,Carruthers, V.B.
Toxoplasma gondii cathepsin L is the primary target of the invasion-inhibitory compound morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl.
J.Biol.Chem., 284:26839-26850, 2009

PubMed Abstract: The protozoan parasite Toxoplasma gondii relies on post-translational modification, including proteolysis, of proteins required for recognition and invasion of host cells. We have characterized the T. gondii cysteine protease cathepsin L (TgCPL), one of five cathepsins found in the T. gondii genome. We show that TgCPL is the primary target of the compound morpholinurea-leucyl-homophenyl-vinyl sulfone phenyl (LHVS), which was previously shown to inhibit parasite invasion by blocking the release of invasion proteins from microneme secretory organelles. As shown by fluorescently labeled LHVS and TgCPL-specific antibodies, TgCPL is associated with a discrete vesicular structure in the apical region of extracellular parasites but is found in multiple puncta throughout the cytoplasm of intracellular replicating parasites. LHVS fails to label cells lacking TgCPL due to targeted disruption of the TgCPL gene in two different parasite strains. We present a structural model for the inhibition of TgCPL by LHVS based on a 2.0 A resolution crystal structure of TgCPL in complex with its propeptide. We discuss possible roles for TgCPL as a protease involved in the degradation or limited proteolysis of parasite proteins involved in invasion.

PubMed: 19596863
DOI: 10.1074/jbc.M109.003780

Experimental method

X-RAY DIFFRACTION (1.99 Å)