3tm0 | pdb_00003tm0

Crystal Structure of 3',5"-Aminoglycoside Phosphotransferase Type IIIa AMPPNP Butirosin A Complex

spinqualitylabelsall models 3tm0, resolution 2.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tm0 is a 1 chain structure with sequence from "enterococcus_proteiformis"_thiercelin_and_jouhaud_1903 "enterococcus proteiformis" thiercelin and jouhaud 1903. This structure supersedes the now removed PDB entry 3h8p. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ANP, B31, MG Related: 1j7i, 1j7l, 1j7u, 1l8t, 2b0q, 3tl7 Gene: aph(3')-iiia, aphA ("Enterococcus proteiformis" Thiercelin and Jouhaud 1903) Activity: Kanamycin kinase, with EC number 2.7.1.95 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KKA3_ENTFL] Resistance to kanamycin and structurally-related aminoglycosides, including amikacin. Publication Abstract from PubMed Butirosin is unique among the naturally occurring aminoglycosides, having a substituted amino group at position 1 (N1) of the 2-deoxystreptamine ring with an (S)-4-amino-2-hydroxybutyrate (AHB) group. While bacterial resistance to aminoglycosides can be ascribed chiefly to drug inactivation by plasmid-encoded aminoglycoside-modifying enzymes, the presence of an AHB group protects the aminoglycoside from binding to many resistance enzymes, and hence, the antibiotic retains its bactericidal properties. Consequently, several semisynthetic N1-substituted aminoglycosides, such as amikacin, isepamicin, and netilmicin, were developed. Unfortunately, butirosin, amikacin, and isepamicin are not resistant to inactivation by 3'-aminoglycoside O-phosphotransferase type IIIa [APH(3')-IIIa]. We report here the crystal structure of APH(3')-IIIa in complex with an ATP analog, AMPPNP [adenosine 5'-(beta,gamma-imido)triphosphate], and butirosin A to 2.4-A resolution. The structure shows that butirosin A binds to the enzyme in a manner analogous to other 4,5-disubstituted aminoglycosides, and the flexible antibiotic-binding loop is key to the accommodation of structurally diverse substrates. Based on the crystal structure, we have also constructed a model of APH(3')-IIIa in complex with amikacin, a commonly used semisynthetic N1-substituted 4,6-disubstituted aminoglycoside. Together, these results suggest a strategy to further derivatize the AHB group in order to generate new aminoglycoside derivatives that can elude inactivation by resistance enzymes while maintaining their ability to bind to the ribosomal A site. Structural basis of APH(3')-IIIa-mediated resistance to N1-substituted aminoglycoside antibiotics.,Fong DH, Berghuis AM Antimicrob Agents Chemother. 2009 Jul;53(7):3049-55. Epub 2009 May 11. PMID:19433564 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphotransferase 3D structures

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