4JD6

Crystal structure of Mycobacterium tuberculosis Eis in complex with coenzyme A and tobramycin

Summary for 4JD6

• Entry DOI: 10.2210/pdb4jd6/pdb
• Descriptor: Enhanced intracellular survival protein, COENZYME A, TOBRAMYCIN (3 entities in total)
• Functional Keywords: gnat, aminoglycoside acetyltransferase, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 6
• Total formula weight: 285505.27

Authors

Biswas, T.,Chen, W.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2013-02-23, release date: 2013-10-23, Last modification date: 2024-02-28)

Primary citation

Houghton, J.L.,Biswas, T.,Chen, W.,Tsodikov, O.V.,Garneau-Tsodikova, S.
Chemical and structural insights into the regioversatility of the aminoglycoside acetyltransferase eis.
Chembiochem, 14:2127-2135, 2013

PubMed Abstract: A recently discovered cause of tuberculosis resistance to a drug of last resort, the aminoglycoside kanamycin, results from modification of this drug by the enhanced intracellular survival (Eis) protein. Eis is a structurally and functionally unique acetyltransferase with an unusual capability of acetylating aminoglycosides at multiple positions. The extent of this regioversatility and its defining protein features are unclear. Herein, we determined the positions and order of acetylation of five aminoglycosides by NMR spectroscopy. This analysis revealed unprecedented acetylation of the 3''-amine of kanamycin, amikacin, and tobramycin, and the γ-amine of the 4-amino-2-hydroxybutyryl group of amikacin. A crystal structure of Eis in complex with coenzyme A and tobramycin revealed how tobramycin can be accommodated in the Eis active site in two binding modes, consistent with its diacetylation. These studies, describing chemical and structural details of acetylation, will guide future efforts towards designing aminoglycosides and Eis inhibitors to overcome resistance in tuberculosis.

PubMed: 24106131
DOI: 10.1002/cbic.201300359

Experimental method

X-RAY DIFFRACTION (3.5 Å)