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A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7.

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 ?-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.

SUBMITTER: Yoon HJ

PROVIDER: S-EPMC3795558 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7.

Yoon Hye Jin HJ Kim Kyoung Hoon KH Yang Jin Kuk JK Suh Se Won SW Kim Hyunsik H Jang Soonmin S

Journal of synchrotron radiation 20131001 Pt 6

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 ...[more]

PMID: 24121342

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Project description:Computational prediction and protein structure modeling have come to the aid of various biological problems in determining the structure of proteins. These technologies have revolutionized the biological world of research, allowing scientists and researchers to gain insights into their biological questions and design experimental research much more efficiently. Pathogenic Mycobacterium spp. is known to stay alive within the macrophages of its host. Mycobacterium tuberculosis is an acid-fast bacterium that is the most common cause of tuberculosis and is considered to be the main cause of resistance of tuberculosis as a leading health issue. The genome of Mycobacterium tuberculosis contains more than 4,000 genes, of which the majority are of unknown function. An attempt has been made to computationally model and dock one of its proteins, Rv1250 (MTV006.22), which is considered as an apparent drug-transporter, integral membrane protein, and member of major facilitator superfamily (MFS). The most widely used techniques, i.e., homology modeling, molecular docking, and molecular dynamics (MD) simulation in the field of structural bioinformatics, have been used in the present work to study the behavior of Rv1250 protein from M. tuberculosis. The structure of unknown TB protein, i.e., Rv1250 was retrived using homology modeling with the help of I-TASSER server. Further, one of the sites responsible for infection was identified and docking was done by using the specific Isoniazid ligand which is an inhibitor of this protein. Finally, the stability of protein model and analysis of stable and static interaction between protein and ligand molecular dynamic simulation was performed at 100 ns The designing of novel Rv1250 enzyme inhibitors is likely achievable with the use of proposed predicted model, which could be helpful in preventing the pathogenesis caused by M. tuberculosis. Finally, the MD simulation was done to evaluate the stability of the ligand for the specific protein.

Dataset Information

A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7.

Publications

A docking study of enhanced intracellular survival protein from Mycobacterium tuberculosis with human DUSP16/MKP-7.

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