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| ==Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor pyrazolopyrimidine PP1== | | ==Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor pyrazolopyrimidine PP1== |
| <StructureSection load='4fev' size='340' side='right' caption='[[4fev]], [[Resolution|resolution]] 1.89Å' scene=''> | | <StructureSection load='4fev' size='340' side='right'caption='[[4fev]], [[Resolution|resolution]] 1.89Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4fev]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Acinetobacter_baumannii_aye Acinetobacter baumannii aye]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FEV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FEV FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4fev]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii_AYE Acinetobacter baumannii AYE]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FEV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FEV FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=KAN:KANAMYCIN+A'>KAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PP1:1-TER-BUTYL-3-P-TOLYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YLAMINE'>PP1</scene></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.89Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ej7|4ej7]], [[4feu|4feu]], [[4few|4few]], [[4fex|4fex]], [[4gkh|4gkh]], [[4gki|4gki]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=KAN:KANAMYCIN+A'>KAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PP1:1-TER-BUTYL-3-P-TOLYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-YLAMINE'>PP1</scene></td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ABAYE3578, APHA1-IAB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=509173 Acinetobacter baumannii AYE])</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=4fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fev OCA], [https://pdbe.org/4fev PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fev RCSB], [https://www.ebi.ac.uk/pdbsum/4fev PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fev 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/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>
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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=4fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fev OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fev RCSB], [http://www.ebi.ac.uk/pdbsum/4fev PDBsum]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/B0VD92_ACIBY B0VD92_ACIBY] |
| Activity of the aminoglycoside phosphotransferase APH(3')-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescuing compromised antibiotics such as aminoglycosides is targeting the enzymes conferring resistance with small molecules. Previously we demonstrated that eukaryotic protein kinase (ePK) inhibitors could inhibit APH enzymes, due to the structural similarity between these two enzyme families. However, limited structural information of enzyme-inhibitor complexes hindered interpretation of the results. As well, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. Here, we structurally and functionally characterize inhibition of APH(3')-Ia by three diverse chemical scaffolds - anthrapyrazolone, 4-anilinoquinazoline and pyrazolopyrimidine (PP) - and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3')-Ia versus ePKs. Using this observation, we identify PP-derivatives that select against ePKs, attenuate APH(3')-Ia activity and rescue aminoglycoside antibiotic activity against a resistant E. coli strain. The structures presented here and these inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance.
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| Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance.,Stogios PJ, Spanogiannopoulos P, Evdokimova E, Egorova O, Shakya T, Todorovic N, Capretta A, Wright GD, Savchenko A Biochem J. 2013 Jun 12. PMID:23758273<ref>PMID:23758273</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Phosphotransferase|Phosphotransferase]] | | *[[Phosphotransferase 3D structures|Phosphotransferase 3D structures]] |
| == References ==
| |
| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Acinetobacter baumannii aye]] | | [[Category: Acinetobacter baumannii AYE]] |
| [[Category: Kanamycin kinase]] | | [[Category: Large Structures]] |
| [[Category: Anderson, W F]] | | [[Category: Anderson WF]] |
| [[Category: Structural genomic]] | | [[Category: Di Leo R]] |
| [[Category: Egorova, O]] | | [[Category: Egorova O]] |
| [[Category: Evdokimova, E]] | | [[Category: Evdokimova E]] |
| [[Category: Leo, R Di]]
| | [[Category: Minasov G]] |
| [[Category: Minasov, G]] | | [[Category: Savchenko A]] |
| [[Category: Savchenko, A]] | | [[Category: Shakya T]] |
| [[Category: Shakya, T]] | | [[Category: Spanogiannopoulos P]] |
| [[Category: Spanogiannopoulos, P]] | | [[Category: Stogios PJ]] |
| [[Category: Stogios, P J]] | | [[Category: Wawrzak Z]] |
| [[Category: Wawrzak, Z]] | | [[Category: Wright GD]] |
| [[Category: Wright, G D]] | |
| [[Category: Alpha/beta protein]]
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| [[Category: Aminoglycoside phosphotransferase]]
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| [[Category: Aminoglycoside]]
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| [[Category: Antibiotic resistance]]
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| [[Category: Csgid]]
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| [[Category: Eukaryotic protein kinase-like fold]]
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| [[Category: Gtp]]
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| [[Category: Intracellular]]
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| [[Category: Kanamycin]]
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| [[Category: National institute of allergy and infectious disease]]
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| [[Category: Niaid]]
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| [[Category: Phosphotransferase]]
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| [[Category: Pp1]]
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| [[Category: Protein kinase inhibitor]]
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| [[Category: Pyrazolopyrimidine]]
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| [[Category: Transferase]]
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| [[Category: Transferase-transferase inhibitor complex]]
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