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| | ==Crystal Structure of Spectinomycin Phosphotransferase, APH(9)-Ia, Protein Kinase Inhibitor CKI-7 Complex== | | ==Crystal Structure of Spectinomycin Phosphotransferase, APH(9)-Ia, Protein Kinase Inhibitor CKI-7 Complex== |
| - | <StructureSection load='3q2m' size='340' side='right' caption='[[3q2m]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='3q2m' size='340' side='right'caption='[[3q2m]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3q2m]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Legionella_pneumophila_130b Legionella pneumophila 130b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3Q2M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3Q2M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3q2m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Legionella_pneumophila_130b Legionella pneumophila 130b]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3Q2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3Q2M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CKI:N-(2-AMINOETHYL)-5-CHLOROISOQUINOLINE-8-SULFONAMIDE'>CKI</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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]] 2.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3i0o|3i0o]], [[3i0q|3i0q]], [[3i1a|3i1a]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CKI:N-(2-AMINOETHYL)-5-CHLOROISOQUINOLINE-8-SULFONAMIDE'>CKI</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">aph, LPW_21961 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=866628 Legionella pneumophila 130b])</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=3q2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3q2m OCA], [https://pdbe.org/3q2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3q2m RCSB], [https://www.ebi.ac.uk/pdbsum/3q2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3q2m ProSAT]</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=3q2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3q2m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3q2m RCSB], [http://www.ebi.ac.uk/pdbsum/3q2m PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/O06916_LEGPN O06916_LEGPN] |
| - | Antibiotic resistance is recognized as a growing healthcare problem. To address this issue, one strategy is to thwart the causal mechanism using an adjuvant in partner with the antibiotic. Aminoglycosides are a class of clinically important antibiotics used for the treatment of serious infections. Their usefulness has been compromised predominantly due to drug inactivation by aminoglycoside-modifying enzymes, such as aminoglycoside phosphotransferases or kinases. These kinases are structurally homologous to eukaryotic Ser/Thr and Tyr protein kinases and it has been shown that some can be inhibited by select protein kinase inhibitors. The aminoglycoside kinase, APH(3')-IIIa, can be inhibited by CKI-7, an ATP-competitive inhibitor for the casein kinase 1. We have determined that CKI-7 is also a moderate inhibitor for the atypical APH(9)-Ia. Here we present the crystal structures of CKI-7-bound APH(3')-IIIa and APH(9)-Ia, the first structures of a eukaryotic protein kinase inhibitor in complex with bacterial kinases. CKI-7 binds to the nucleotide-binding pocket of the enzymes and its binding alters the conformation of the nucleotide-binding loop, the segment homologous to the glycine-rich loop in eukaryotic protein kinases. Comparison of these structures with the CKI-7-bound casein kinase 1 reveals features in the binding pockets that are distinct in the bacterial kinases and could be exploited for the design of a bacterial kinase specific inhibitor. Our results provide evidence that an inhibitor for a subset of APHs can be developed in order to curtail resistance to aminoglycosides.
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| - | Crystal structures of two aminoglycoside kinases bound with a eukaryotic protein kinase inhibitor.,Fong DH, Xiong B, Hwang J, Berghuis AM PLoS One. 2011 May 9;6(5):e19589. doi: 10.1371/journal.pone.0019589. PMID:21573013<ref>PMID:21573013</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: Large Structures]] |
| | [[Category: Legionella pneumophila 130b]] | | [[Category: Legionella pneumophila 130b]] |
| - | [[Category: Berghuis, A M]] | + | [[Category: Berghuis AM]] |
| - | [[Category: Fong, D H]] | + | [[Category: Fong DH]] |
| - | [[Category: Hwang, J]] | + | [[Category: Hwang J]] |
| - | [[Category: Xiong, B]] | + | [[Category: Xiong B]] |
| - | [[Category: Cytosol]]
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| - | [[Category: Phosphorylation]]
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| - | [[Category: Phosphotransferase]]
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| - | [[Category: Ser/thr/tyr protein kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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