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| | ==Solution Structure of Antibiotic-Resistance Factor ANT(2'')-Ia Reveals Substrate-Regulated Conformation Dynamics== | | ==Solution Structure of Antibiotic-Resistance Factor ANT(2'')-Ia Reveals Substrate-Regulated Conformation Dynamics== |
| - | <StructureSection load='5kqj' size='340' side='right' caption='[[5kqj]], [[NMR_Ensembles_of_Models | 15 NMR models]]' scene=''> | + | <StructureSection load='5kqj' size='340' side='right'caption='[[5kqj]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5kqj]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KQJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KQJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5kqj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KQJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KQJ FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">aadB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5kqj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kqj OCA], [https://pdbe.org/5kqj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kqj RCSB], [https://www.ebi.ac.uk/pdbsum/5kqj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kqj ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.46 2.7.7.46] </span></td></tr>
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| - | <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=5kqj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kqj OCA], [http://pdbe.org/5kqj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kqj RCSB], [http://www.ebi.ac.uk/pdbsum/5kqj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kqj ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AADB1_KLEPN AADB1_KLEPN]] This enzyme confers resistance to kanamycin, gentamicin, dibekacin, sisomicin and tobramycin by adenylating the 2''-hydroxyl group of these antibiotics. | + | [https://www.uniprot.org/uniprot/AADB1_KLEPN AADB1_KLEPN] This enzyme confers resistance to kanamycin, gentamicin, dibekacin, sisomicin and tobramycin by adenylating the 2''-hydroxyl group of these antibiotics. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Transferase]] | + | [[Category: Klebsiella pneumoniae]] |
| - | [[Category: Bacot-Davis, V R]] | + | [[Category: Large Structures]] |
| - | [[Category: Berghuis, A M]] | + | [[Category: Bacot-Davis VR]] |
| - | [[Category: Aminoglycoside]] | + | [[Category: Berghuis AM]] |
| - | [[Category: Antibiotic resistance]]
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| Structural highlights
Function
AADB1_KLEPN This enzyme confers resistance to kanamycin, gentamicin, dibekacin, sisomicin and tobramycin by adenylating the 2-hydroxyl group of these antibiotics.
Publication Abstract from PubMed
The aminoglycoside modifying enzyme (AME) ANT(2)-Ia is a significant target for next generation antibiotic development. Structural studies of a related aminoglycoside-modifying enzyme, ANT(3)(9), revealed this enzyme contains dynamic, disordered, and well-defined segments that modulate thermodynamically before and after antibiotic binding. Characterizing these structural dynamics is critical for in situ screening, design, and development of contemporary antibiotics that can be implemented in a clinical setting to treat potentially lethal, antibiotic resistant, human infections. Here, the first NMR structural ensembles of ANT(2)-Ia are presented, and suggest that ATP-aminoglycoside binding repositions the nucleotidyltransferase (NT) and C-terminal domains for catalysis to efficiently occur. Residues involved in ligand recognition were assessed by site-directed mutagenesis. In vitro activity assays indicate a critical role for I129 toward aminoglycoside modification in addition to known catalytic D44, D46, and D48 residues. These observations support previous claims that ANT aminoglycoside sub-class promiscuity is not solely due to binding cleft size, or inherent partial disorder, but can be controlled by ligand modulation on distinct dynamic and thermodynamic properties of ANTs under cellular conditions. Hydrophobic interactions in the substrate binding cleft, as well as solution dynamics in the C-terminal tail of ANT(2)-Ia, advocate toward design of kanamycin-derived cationic lipid aminoglycoside analogs, some of which have already shown antimicrobial activity in vivo against kanamycin and gentamicin-resistant P. aeruginosa. This data will drive additional in silico, next generation antibiotic development for future human use to combat increasingly prevalent antimicrobial resistance.
Effect of solvent and protein dynamics in ligand recognition and inhibition of aminoglycoside adenyltransferase 2-Ia.,Bacot-Davis VR, Bassenden AV, Sprules T, Berghuis AM Protein Sci. 2017 Sep;26(9):1852-1863. doi: 10.1002/pro.3224. Epub 2017 Jul 21. PMID:28734024[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bacot-Davis VR, Bassenden AV, Sprules T, Berghuis AM. Effect of solvent and protein dynamics in ligand recognition and inhibition of aminoglycoside adenyltransferase 2-Ia. Protein Sci. 2017 Sep;26(9):1852-1863. doi: 10.1002/pro.3224. Epub 2017 Jul 21. PMID:28734024 doi:http://dx.doi.org/10.1002/pro.3224
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