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[[ | ==Crystal Structure of 3',5"-Aminoglycoside Phosphotransferase Type IIIa AMPPNP Butirosin A Complex== | ||
<StructureSection load='3tm0' size='340' side='right' caption='[[3tm0]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3tm0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Enterococcus_faecalis Enterococcus faecalis]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3h8p 3h8p]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TM0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TM0 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ANP:PHOSPHOAMINOPHOSPHONIC+ACID-ADENYLATE+ESTER'>ANP</scene>, <scene name='pdbligand=B31:(2S)-4-AMINO-N-[(1R,2S,3R,4R,5S)-5-AMINO-4-[(2,6-DIAMINO-2,6-DIDEOXY-ALPHA-D-GLUCOPYRANOSYL)OXY]-2-HYDROXY-3-(BETA-D-XYLOFURANOSYLOXY)CYCLOHEXYL]-2-HYDROXYBUTANAMIDE'>B31</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1j7i|1j7i]], [[1j7l|1j7l]], [[1j7u|1j7u]], [[1l8t|1l8t]], [[2b0q|2b0q]], [[3tl7|3tl7]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">aph(3')-iiia, aphA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1351 Enterococcus faecalis])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Kanamycin_kinase Kanamycin kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.95 2.7.1.95] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tm0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tm0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3tm0 RCSB], [http://www.ebi.ac.uk/pdbsum/3tm0 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:19433564</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Phosphotransferase|Phosphotransferase]] | *[[Phosphotransferase|Phosphotransferase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Enterococcus faecalis]] | [[Category: Enterococcus faecalis]] | ||
[[Category: Kanamycin kinase]] | [[Category: Kanamycin kinase]] | ||
[[Category: Berghuis, A M | [[Category: Berghuis, A M]] | ||
[[Category: Fong, D H | [[Category: Fong, D H]] | ||
[[Category: Phosphorylation]] | [[Category: Phosphorylation]] | ||
[[Category: Protein kinase]] | [[Category: Protein kinase]] | ||
[[Category: Transferase-antibiotic complex]] | [[Category: Transferase-antibiotic complex]] | ||
Revision as of 18:22, 9 December 2014
Crystal Structure of 3',5"-Aminoglycoside Phosphotransferase Type IIIa AMPPNP Butirosin A ComplexCrystal Structure of 3',5"-Aminoglycoside Phosphotransferase Type IIIa AMPPNP Butirosin A Complex
Structural highlights
Publication Abstract from PubMedButirosin 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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