Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas' disease

Abstract

Chagas' disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore a promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed.

Figure 1

Stereo view of the three-dimensional structure of T. cruzi TcPTP1 with secondary structure elements colored as follows: helix (cyan), loop (magenta), sheet (red).

Figure 2

Ribbon model (A) and space-filling model (B) of TcPTP1. Trypanasomatid-specific motifs are colored in red. Residues found in the catalytic P loop, the Q loop and the WPD loop are colored blue.

Figure 3

The final 2F_o-F_c electron density map (blue, 2.18 Å resolution, contoured at 1.0 σ level) superimposed onto the TcPTP1 active site residues (carbon in gray, nitrogen in blue, oxygen in red, and sulfur in yellow). A formate molecule (carbon in cyan), from the crystallization solution, was found in the active site of chain A.

Figure 4

Stereo views of the crystal structure of TcPTP1 (cyan) superimposed onto the structures of (A) T. brucei TbPTP1 (red, PDB code: 3m4u) and (B) human PTP1B (wheat, PDB code: 2hnq).

Figure 5

The active site residues of TcPTP1 (carbon in gray, nitrogen in blue, oxygen in red, and sulfur in yellow) are aligned with the corresponding residues of human PTP1B (carbon in cyan, PDB code: 2hnq).

Figure 6

The electrostatic surface potentials (positive in blue, negative in red) of (A) Y. pestis YopH (PDB code: 2y2f), (B) T. cruzi TcPTP1, and (C) human PTP1B (PDB code: 2hnq). An aminooxy-containing platform compound used to develop bidentate inhibitors of YopH is shown in the crystal structure of YopH (A) and modeled in the TcPTP1 and hPTP1B active sites (B-C). Secondary pockets P1 and P2 located adjacent to the active sites of the PTPases are indicated by the arrows.