Abstract
The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis, and one of its secreted effector proteins, called enhanced intracellular survival (Eis) protein, enhances its survival in macrophages. Mtb Eis activates JNK-specific dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7) through the acetylation on Lys55, thus inactivating JNK by dephosphorylation. Based on the recently reported crystal structure of Mtb Eis, a docking model for the binding of Mtb Eis to DUSP16/MKP-7 was generated. In the docking model, the substrate helix containing Lys55 of DUSP16/MKP-7 fits nicely into the active-site cleft of Mtb Eis; the twisted β-sheet of Eis domain II embraces the substrate helix from one side. Most importantly, the side-chain of Lys55 is inserted toward acetyl-CoA and the resulting distance is 4.6 Å between the NZ atom of Lys55 and the carbonyl carbon of the acetyl group in acetyl-CoA. The binding of Mtb Eis and DUSP16/MKP-7 is maintained by strong electrostatic interactions. The active-site cleft of Mtb Eis has a negatively charged surface formed by Asp25, Glu138, Asp286, Glu395 and the terminal carboxylic group of Phe396. In contrast, DUSP16/MKP-7 contains five basic residues, Lys52, Lys55, Arg56, Arg57 and Lys62, which point toward the negatively charged surface of the active-site pocket of Mtb Eis. Thus, the current docking model suggests that the binding of DUSP16/MKP-7 to Mtb Eis should be established by charge complementarity in addition to a very favorable geometric arrangement. The suggested mode of binding requires the dissociation of the hexameric Mtb Eis into dimers or monomers. This study may be useful for future studies aiming to develop inhibitors of Mtb Eis as a new anti-tuberculosis drug candidate.
Highlights
Tuberculosis, caused by pathogenic bacterium Mycobacterium tuberculosis (Mtb), is difficult to treat and increasing drugresistance poses a serious global health threat (Dye & Williams, 2010; Chiang et al, 2010)
We recently revealed the molecular mechanism by which Mtb enhanced intracellular survival (Eis) down-regulates JNK and thereby enhances Mtb survival (Kim et al, 2012)
The starting structure of Mtb Eis with acetyl-CoA was obtained from our previous study (PDB code: 3ryo) and the dual-specificity protein phosphatase 16 (DUSP16)/ mitogenactivated protein kinase phosphatase-7 (MKP-7) structure was taken from the Protein Data Bank (PDB)
Summary
Tuberculosis, caused by pathogenic bacterium Mycobacterium tuberculosis (Mtb), is difficult to treat and increasing drugresistance poses a serious global health threat (Dye & Williams, 2010; Chiang et al, 2010) This raises the urgent need for developing a new class of anti-tuberculosis drugs, which prompts the identification of novel drug target proteins of Mtb. Since one of survival strategies of Mtb is to inhibit the phagosomal maturation and autophagy in macrophages, Mtb effector proteins involved in these processes are of great. The docked model suggests that the helix harboring Lys of DUSP16/ MKP-7 fits into the active-site cleft of Mtb Eis and the binding may be established by the structural fit and the electrostatic complementarity. This study may provide the structural basis for future research aiming to develop the inhibitor of Mtb Eis as a new tuberculosis drug
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