title: Structure of Mycobacterium smegmatis Eis in complex with paromomycin.
abstract: The Rv2416c gene of Mycobacterium tuberculosis (Mtb) encodes the enhanced intracellular survival (Eis) protein that enhances intracellular survival of the pathogen in host macrophages during infection. The Mtb Eis protein is released into the cytoplasm of the phagocyte during intracellular infection and modulates the host immune response. It also contributes to drug resistance by acetylating multiple amine groups of aminoglycosides. Interestingly, the nonpathogenic M. smegmatis (Msm) contains a homologous eis gene (MSMEG_3513). The overall structures of Mtb Eis and Msm Eis are highly similar to each other, reflecting the high level (58%) of amino-acid sequence identity between them. Both Mtb Eis and Msm Eis are active as aminoglycoside acetyltransferases, while only Mtb Eis functions as an N(ℇ)-acetyltransferase to acetylate Lys55 of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase 7 (MKP-7), leading to the suppression of host immune responses. Here, the crystal structure of Msm Eis in the paromomycin-bound form is reported, revealing detailed interactions between an aminoglycoside antibiotic and Msm Eis. The crystal structure of Msm Eis in the paromomycin-bound form has been determined at 3.3 Å resolution. This work provides potentially useful information for structure-guided discovery of Eis inhibitors as a novel antituberculosis drug against drug-resistant Mtb.
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyoung Hoon
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: An
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Department of Chemistry, College of Natural Sciences, Soongsil University, Seoul 156-743, Republic of Korea.
authors.forename: Jin Kuk
authors.initials: JK
authors.lastname: Yang
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Se Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D020102:Mycobacterium smegmatis / Q000737:chemistry*; D010303:Paromomycin / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D010303:Paromomycin
keywords: Mycobacterium smegmatis; Mycobacterium tuberculosis; aminoglycoside; drug resistance; paromomycin; tobramycin; tuberculosis