2bkk

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[[Image:2bkk.gif|left|200px]]<br /><applet load="2bkk" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2bkk, resolution 2.15&Aring;" />
 
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'''CRYSTAL STRUCTURE OF AMINOGLYCOSIDE PHOSPHOTRANSFERASE APH (3')-IIIA IN COMPLEX WITH THE INHIBITOR AR_3A'''<br />
 
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==Overview==
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==Crystal structure of Aminoglycoside Phosphotransferase APH(3')-IIIa in complex with the inhibitor AR_3a==
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Aminoglycoside phosphotransferase (3')-IIIa (APH) is a bacterial kinase, that confers antibiotic resistance to many pathogenic bacteria and shares, structural homology with eukaryotic protein kinases. We report here the, crystal structure of APH, trapped in an inactive conformation by a, tailor-made inhibitory ankyrin repeat (AR) protein, at 2.15 A resolution., The inhibitor was selected from a combinatorial library of designed AR, proteins. The AR protein binds the C-terminal lobe of APH and thereby, stabilizes three alpha helices, which are necessary for substrate binding, in a significantly displaced conformation. BIAcore analysis and kinetic, enzyme inhibition experiments are consistent with the proposed allosteric, inhibition mechanism. In contrast to most small-molecule kinase, inhibitors, the AR proteins are not restricted to active site binding, allowing for higher specificity. Inactive conformations of, pharmaceutically relevant enzymes, as can be elucidated with the approach, presented here, represent powerful starting points for rational drug, design.
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<StructureSection load='2bkk' size='340' side='right'caption='[[2bkk]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2bkk]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/"enterococcus_proteiformis"_thiercelin_and_jouhaud_1903 "enterococcus proteiformis" thiercelin and jouhaud 1903] and [https://en.wikipedia.org/wiki/Synthetic_construct_sequences Synthetic construct sequences]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BKK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BKK FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1k1a|1k1a]], [[1k1b|1k1b]], [[1mj0|1mj0]], [[1n0q|1n0q]], [[1n0r|1n0r]], [[1j7i|1j7i]], [[1j7l|1j7l]], [[1j7u|1j7u]], [[1l8t|1l8t]], [[1l8u|1l8u]], [[2bkg|2bkg]]</div></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Kanamycin_kinase Kanamycin kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2bkk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bkk OCA], [https://pdbe.org/2bkk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bkk RCSB], [https://www.ebi.ac.uk/pdbsum/2bkk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bkk ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/KKA3_ENTFL KKA3_ENTFL]] Resistance to kanamycin and structurally-related aminoglycosides, including amikacin.
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bk/2bkk_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bkk ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Aminoglycoside phosphotransferase (3')-IIIa (APH) is a bacterial kinase that confers antibiotic resistance to many pathogenic bacteria and shares structural homology with eukaryotic protein kinases. We report here the crystal structure of APH, trapped in an inactive conformation by a tailor-made inhibitory ankyrin repeat (AR) protein, at 2.15 A resolution. The inhibitor was selected from a combinatorial library of designed AR proteins. The AR protein binds the C-terminal lobe of APH and thereby stabilizes three alpha helices, which are necessary for substrate binding, in a significantly displaced conformation. BIAcore analysis and kinetic enzyme inhibition experiments are consistent with the proposed allosteric inhibition mechanism. In contrast to most small-molecule kinase inhibitors, the AR proteins are not restricted to active site binding, allowing for higher specificity. Inactive conformations of pharmaceutically relevant enzymes, as can be elucidated with the approach presented here, represent powerful starting points for rational drug design.
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==About this Structure==
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Allosteric inhibition of aminoglycoside phosphotransferase by a designed ankyrin repeat protein.,Kohl A, Amstutz P, Parizek P, Binz HK, Briand C, Capitani G, Forrer P, Pluckthun A, Grutter MG Structure. 2005 Aug;13(8):1131-41. PMID:16084385<ref>PMID:16084385</ref>
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2BKK is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Enterococcus_faecalis Enterococcus faecalis] with MG and ADP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Site: <scene name='pdbsite=AC1:Mg Binding Site For Chain C'>AC1</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BKK OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Allosteric inhibition of aminoglycoside phosphotransferase by a designed ankyrin repeat protein., Kohl A, Amstutz P, Parizek P, Binz HK, Briand C, Capitani G, Forrer P, Pluckthun A, Grutter MG, Structure. 2005 Aug;13(8):1131-41. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16084385 16084385]
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</div>
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[[Category: Enterococcus faecalis]]
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<div class="pdbe-citations 2bkk" style="background-color:#fffaf0;"></div>
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[[Category: Kanamycin kinase]]
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[[Category: Protein complex]]
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[[Category: Amstutz, P.]]
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[[Category: Binz, H.K.]]
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[[Category: Briand, C.]]
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[[Category: Capitani, G.]]
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[[Category: Forrer, P.]]
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[[Category: Grutter, M.G.]]
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[[Category: Kohl, A.]]
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[[Category: Parizek, P.]]
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[[Category: Pluckthun, A.]]
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[[Category: ADP]]
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[[Category: MG]]
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[[Category: ankyrin repeat]]
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[[Category: antibiotic resistance]]
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[[Category: atp-binding]]
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[[Category: co-crystallization]]
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[[Category: designed repeat protein]]
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[[Category: drug design]]
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[[Category: enzyme inhibition]]
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[[Category: inhibitor design]]
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[[Category: kinase]]
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[[Category: kinase inhibition]]
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[[Category: plasmid]]
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[[Category: transferase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 18:50:11 2007''
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==See Also==
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*[[Phosphotransferase 3D structures|Phosphotransferase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Enterococcus proteiformis thiercelin and jouhaud 1903]]
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[[Category: Kanamycin kinase]]
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[[Category: Large Structures]]
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[[Category: Synthetic construct sequences]]
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[[Category: Amstutz, P]]
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[[Category: Binz, H K]]
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[[Category: Briand, C]]
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[[Category: Capitani, G]]
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[[Category: Forrer, P]]
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[[Category: Grutter, M G]]
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[[Category: Kohl, A]]
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[[Category: Parizek, P]]
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[[Category: Pluckthun, A]]
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[[Category: Ankyrin repeat]]
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[[Category: Antibiotic resistance]]
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[[Category: Atp-binding]]
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[[Category: Co-crystallization]]
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[[Category: Designed repeat protein]]
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[[Category: Drug design]]
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[[Category: Enzyme inhibition]]
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[[Category: Inhibitor design]]
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[[Category: Kinase]]
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[[Category: Kinase inhibition]]
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[[Category: Plasmid]]
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[[Category: Transferase]]
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[[Category: Transferase-designed protein complex]]
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[[Category: Transferase-peptide complex]]
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[[Category: Transferase/peptide]]

Current revision

Crystal structure of Aminoglycoside Phosphotransferase APH(3')-IIIa in complex with the inhibitor AR_3a

PDB ID 2bkk

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