4fev - Revision history

OCA at 15:23, 14 March 2024

2024-03-14T15:23:20Z

← Older revision		Revision as of 15:23, 14 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<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>		<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" 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>		</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='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='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='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>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/B0VD92_ACIBY B0VD92_ACIBY]		[https://www.uniprot.org/uniprot/B0VD92_ACIBY B0VD92_ACIBY]
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	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.

	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>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4fev" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==
	*[[Phosphotransferase 3D structures\|Phosphotransferase 3D structures]]		*[[Phosphotransferase 3D structures\|Phosphotransferase 3D structures]]
	~~== References ==~~
	~~<references/>~~
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 04:53, 7 October 2022

2022-10-07T04:53:04Z

← Older revision		Revision as of 04:53, 7 October 2022
Line 1:		Line 1:

	==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/~~Aciby Aciby~~]. 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='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='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='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='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 ACIBY])</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=4fev FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fev OCA], [~~http~~://pdbe.org/4fev PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4fev RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4fev PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4fev ProSAT]</span></td></tr>
	</table>		</table>
			== Function ==
			[https://www.uniprot.org/uniprot/B0VD92_ACIBY B0VD92_ACIBY]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 20:

	==See Also==		==See Also==
	*[[Phosphotransferase\|Phosphotransferase]]		*[[Phosphotransferase 3D structures\|Phosphotransferase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Aciby~~]]		[[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]]~~
	~~[[Category: Aminoglycoside phosphotransferase]]~~
	~~[[Category: Aminoglycoside]]~~
	~~[[Category: Antibiotic resistance]]~~
	~~[[Category: Csgid]]~~
	~~[[Category: Eukaryotic protein kinase-like fold]]~~
	~~[[Category: Gtp]]~~
	~~[[Category: Intracellular]]~~
	~~[[Category: Kanamycin]]~~
	~~[[Category: National institute of allergy and infectious disease]]~~
	~~[[Category: Niaid]]~~
	~~[[Category: Phosphotransferase]]~~
	~~[[Category: Pp1]]~~
	~~[[Category: Protein kinase inhibitor]]~~
	~~[[Category: Pyrazolopyrimidine]]~~
	~~[[Category: Transferase]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 18:52, 4 August 2016

2016-08-04T18:52:40Z

← Older revision		Revision as of 18:52, 4 August 2016
Line 1:		Line 1:

	==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 [http://en.wikipedia.org/wiki/Aciby Aciby]. 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>
	</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='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>
	<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='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='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='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 ACIBY])</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='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=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>		<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://pdbe.org/4fev PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fev RCSB], [http://www.ebi.ac.uk/pdbsum/4fev PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fev ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
Line 17:		Line 18:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
			<div class="pdbe-citations 4fev" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 24:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Acinetobacter baumannii aye~~]]		[[Category: Aciby]]
	[[Category: Kanamycin kinase]]		[[Category: Kanamycin kinase]]
	[[Category: Anderson, W F]]		[[Category: Anderson, W F]]

OCA at 11:44, 21 December 2014

2014-12-21T11:44:50Z

← Older revision		Revision as of 11:44, 21 December 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4fev\| PDB=4fev \| SCENE= }}~~		==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=''>
	~~{{ABSTRACT_PUBMED_23758273}}~~		== 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>
			</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>
			<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='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='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=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>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			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.

	~~==About this~~ Structure==		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>
	~~[[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].~~
			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>

	==See Also==		==See Also==
	*[[Phosphotransferase\|Phosphotransferase]]		*[[Phosphotransferase\|Phosphotransferase]]
			== References ==
	==~~Reference~~==		<references/>
	~~<ref group="xtra">PMID:023758273</ref>~~<references ~~group="xtra"~~/><~~references~~/>		__TOC__
			</StructureSection>
	[[Category: Acinetobacter baumannii aye]]		[[Category: Acinetobacter baumannii aye]]
	[[Category: Kanamycin kinase]]		[[Category: Kanamycin kinase]]
	[[Category: Anderson, W F.]]		[[Category: Anderson, W F]]
	[[Category: ~~CSGID, Center for~~ Structural ~~Genomics of Infectious Diseases.~~]]		[[Category: Structural genomic]]
	[[Category: Egorova, O.]]		[[Category: Egorova, O]]
	[[Category: Evdokimova, E.]]		[[Category: Evdokimova, E]]
	[[Category: Leo, R Di.]]		[[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, P J.]]		[[Category: Stogios, P J]]
	[[Category: Wawrzak, Z.]]		[[Category: Wawrzak, Z]]
	[[Category: Wright, G D.]]		[[Category: Wright, G D]]
	[[Category: Alpha/beta protein]]		[[Category: Alpha/beta protein]]
	[[Category: Aminoglycoside phosphotransferase]]		[[Category: Aminoglycoside phosphotransferase]]
	[[Category: Aminoglycoside]]		[[Category: Aminoglycoside]]
	[[Category: Antibiotic resistance]]		[[Category: Antibiotic resistance]]
	~~[[Category: Center for structural genomics of infectious disease]]~~
	[[Category: Csgid]]		[[Category: Csgid]]
	[[Category: Eukaryotic protein kinase-like fold]]		[[Category: Eukaryotic protein kinase-like fold]]

OCA at 19:24, 7 August 2013

2013-08-07T19:24:46Z

← Older revision		Revision as of 19:24, 7 August 2013
Line 5:		Line 5:
	==About this Structure==		==About this Structure==
	[[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].		[[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].

			==See Also==
			*[[Phosphotransferase\|Phosphotransferase]]

	==Reference==		==Reference==

OCA at 07:56, 30 June 2013

2013-06-30T07:56:15Z

← Older revision		Revision as of 07:56, 30 June 2013
Line 1:		Line 1:
	~~[[Image:4fev.png\|left\|200px]]~~

	{{STRUCTURE_4fev\| PDB=4fev \| SCENE= }}		{{STRUCTURE_4fev\| PDB=4fev \| SCENE= }}

	===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===
			{{ABSTRACT_PUBMED_23758273}}

			==About this Structure==
			[[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].

	==~~About this Structure~~==		==Reference==
	~~[[4fev]] is a 6 chain structure with sequence from [http~~://~~en.wikipedia.org/wiki~~/~~Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FEV OCA].~~		<ref group="xtra">PMID:023758273</ref><references group="xtra"/><references/>
	[[Category: Acinetobacter baumannii]]		[[Category: Acinetobacter baumannii aye]]
	[[Category: Kanamycin kinase]]		[[Category: Kanamycin kinase]]
	[[Category: Anderson, W F.]]		[[Category: Anderson, W F.]]

OCA at 06:36, 3 October 2012

2012-10-03T06:36:14Z

← Older revision		Revision as of 06:36, 3 October 2012
Line 1:		Line 1:
	[[Image:4fev.~~jpg~~\|left\|200px]]		[[Image:4fev.png\|left\|200px]]

	{{STRUCTURE_4fev\| PDB=4fev \| SCENE= }}		{{STRUCTURE_4fev\| PDB=4fev \| SCENE= }}

OCA at 08:01, 20 June 2012

2012-06-20T08:01:16Z

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+[[Image:4fev.jpg|left|200px]]
-The entry 4fev is ON HOLD
+{{STRUCTURE_4fev|  PDB=4fev  |  SCENE=  }}
-Authors: Stogios, P.J., Evdokimova, E., Wawrzak, Z., Minasov, G., Egorova, O., Di Leo, R., Shakya, T., Spanogiannopoulos, P., Wright, G.D., Savchenko, A., Anderson, W.F., Center for Structural Genomics of Infectious Diseases (CSGID)
+===Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor pyrazolopyrimidine PP1===
-Description: Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor pyrazolopyrimidine PP1

OCA: Protected "4fev" [edit=sysop:move=sysop]

2012-06-06T07:23:32Z

Protected "4fev" [edit=sysop:move=sysop]

← Older revision	Revision as of 07:23, 6 June 2012
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4fev is ON HOLD Authors: Stogios, P.J., Evdokimova, E., Wawrzak, Z., Minasov, G., Egorova, O., Di Leo, R., Shakya, T., Spanogiannopoulos, P., Wright...

2012-06-06T07:23:31Z

New page: '''Unreleased structure''' The entry 4fev is ON HOLD Authors: Stogios, P.J., Evdokimova, E., Wawrzak, Z., Minasov, G., Egorova, O., Di Leo, R., Shakya, T., Spanogiannopoulos, P., Wright...

New page

'''Unreleased structure'''

The entry 4fev is ON HOLD

Authors: Stogios, P.J., Evdokimova, E., Wawrzak, Z., Minasov, G., Egorova, O., Di Leo, R., Shakya, T., Spanogiannopoulos, P., Wright, G.D., Savchenko, A., Anderson, W.F., Center for Structural Genomics of Infectious Diseases (CSGID)

Description: Crystal structure of the aminoglycoside phosphotransferase APH(3')-Ia, with substrate kanamycin and small molecule inhibitor pyrazolopyrimidine PP1