6oz5: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==== | ==Escherichia coli tRNA synthetase in complex with compound 3== | ||
<StructureSection load='6oz5' size='340' side='right'caption='[[6oz5]]' scene=''> | <StructureSection load='6oz5' size='340' side='right'caption='[[6oz5]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[6oz5]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_str._K-12_substr._MG1655 Escherichia coli str. K-12 substr. MG1655]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OZ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OZ5 FirstGlance]. <br> | ||
</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=6oz5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oz5 OCA], [https://pdbe.org/6oz5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oz5 RCSB], [https://www.ebi.ac.uk/pdbsum/6oz5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oz5 ProSAT]</span></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]] 2.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=VB3:2-({[(2S)-1-cyclohexylpropan-2-yl]amino}methyl)phenol'>VB3</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=6oz5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oz5 OCA], [https://pdbe.org/6oz5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oz5 RCSB], [https://www.ebi.ac.uk/pdbsum/6oz5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oz5 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/SYFA_ECOLI SYFA_ECOLI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Antibiotics to treat drug-resistant Gram-negative infections are urgently needed but challenging to discover. Using a cell-based screen, we identified a simple secondary amine that inhibited the growth of wild-type Escherichia coli and Acinetobacter baumannii but not the growth of the Gram-positive organism Bacillus subtilis. Resistance mutations in E. coli and A. baumannii mapped exclusively to the aminoacyl-tRNA synthetase PheRS. We confirmed biochemically that the compound inhibited PheRS from these organisms and showed that it did not inhibit PheRS from B. subtilis or humans. To understand the basis for the compound's high selectivity for only some PheRS enzymes, we solved crystal structures of E. coli and A. baumannii PheRS complexed with the inhibitor. The structures showed that the compound's benzyl group mimics the benzyl of phenylalanine. The other amine substituent, a 2-(cyclohexen-1-yl)ethyl group, induces a hydrophobic pocket in which it binds. Through bioinformatic analysis and mutagenesis, we show that the ability to induce a complementary hydrophobic pocket that can accommodate the second substituent explains the high selectivity of this remarkably simple molecular scaffold for Gram-negative PheRS. Because this secondary amine scaffold is active against wild-type Gram-negative pathogens but is not cytotoxic to mammalian cells, we suggest that it may be possible to develop it for use in combination antibiotic therapy to treat Gram-negative infections. | |||
Simple Secondary Amines Inhibit Growth of Gram-Negative Bacteria through Highly Selective Binding to Phenylalanyl-tRNA Synthetase.,Baidin V, Owens TW, Lazarus MB, Kahne D J Am Chem Soc. 2021 Jan 20;143(2):623-627. doi: 10.1021/jacs.0c11113. Epub 2021 , Jan 7. PMID:33411531<ref>PMID:33411531</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6oz5" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Aminoacyl tRNA synthetase 3D structures|Aminoacyl tRNA synthetase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Escherichia coli str. K-12 substr. MG1655]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Baidin V]] | ||
[[Category: Kahne D]] | |||
[[Category: Owens TW]] | |||
Latest revision as of 10:20, 11 October 2023
Escherichia coli tRNA synthetase in complex with compound 3Escherichia coli tRNA synthetase in complex with compound 3
Structural highlights
FunctionPublication Abstract from PubMedAntibiotics to treat drug-resistant Gram-negative infections are urgently needed but challenging to discover. Using a cell-based screen, we identified a simple secondary amine that inhibited the growth of wild-type Escherichia coli and Acinetobacter baumannii but not the growth of the Gram-positive organism Bacillus subtilis. Resistance mutations in E. coli and A. baumannii mapped exclusively to the aminoacyl-tRNA synthetase PheRS. We confirmed biochemically that the compound inhibited PheRS from these organisms and showed that it did not inhibit PheRS from B. subtilis or humans. To understand the basis for the compound's high selectivity for only some PheRS enzymes, we solved crystal structures of E. coli and A. baumannii PheRS complexed with the inhibitor. The structures showed that the compound's benzyl group mimics the benzyl of phenylalanine. The other amine substituent, a 2-(cyclohexen-1-yl)ethyl group, induces a hydrophobic pocket in which it binds. Through bioinformatic analysis and mutagenesis, we show that the ability to induce a complementary hydrophobic pocket that can accommodate the second substituent explains the high selectivity of this remarkably simple molecular scaffold for Gram-negative PheRS. Because this secondary amine scaffold is active against wild-type Gram-negative pathogens but is not cytotoxic to mammalian cells, we suggest that it may be possible to develop it for use in combination antibiotic therapy to treat Gram-negative infections. Simple Secondary Amines Inhibit Growth of Gram-Negative Bacteria through Highly Selective Binding to Phenylalanyl-tRNA Synthetase.,Baidin V, Owens TW, Lazarus MB, Kahne D J Am Chem Soc. 2021 Jan 20;143(2):623-627. doi: 10.1021/jacs.0c11113. Epub 2021 , Jan 7. PMID:33411531[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||