6oi8: Difference between revisions
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==Crystal Structure of Haemophilus Influenzae Biotin Carboxylase Complexed with 7-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2-chloro-6-(pyridin-3-yl)phenyl)pyrido[2,3-d]pyrimidin-2-amine== | |||
<StructureSection load='6oi8' size='340' side='right'caption='[[6oi8]], [[Resolution|resolution]] 2.50Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6oi8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OI8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OI8 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MQV:7-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(pyridin-3-yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine'>MQV</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rzq|4rzq]], [[4mv1|4mv1]], [[4mv3|4mv3]], [[4mv4|4mv4]], [[4mv6|4mv6]], [[4mv7|4mv7]], [[4mv8|4mv8]], [[4mv9|4mv9]]</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=6oi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oi8 OCA], [http://pdbe.org/6oi8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oi8 RCSB], [http://www.ebi.ac.uk/pdbsum/6oi8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oi8 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ACCC_HAEIN ACCC_HAEIN]] This protein is a component of the acetyl coenzyme A carboxylase complex; first, biotin carboxylase catalyzes the carboxylation of the carrier protein and then the transcarboxylase transfers the carboxyl group to form malonyl-CoA. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against E. coli and P. aeruginosa, respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in P. aeruginosa occurs at very low frequencies between 10-8 to 10-9. However, resistant isolates had alarmingly high MIC shifts (16 to >128-fold) compared to the parent strain. Whole genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance. | |||
Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase.,Andrews LD, Kane TR, Dozzo P, Haglund CM, Hilderbrandt DJ, Linsell MS, Machajewski T, McEnroe G, Serio AW, Wlasichuk KB, Neau DB, Pakhomova S, Waldrop GL, Sharp M, Pogliano J, Cirz R, Cohen F J Med Chem. 2019 Jul 15. doi: 10.1021/acs.jmedchem.9b00625. PMID:31306011<ref>PMID:31306011</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6oi8" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Andrews, L D]] | |||
[[Category: Cirz, R]] | [[Category: Cirz, R]] | ||
[[Category: Cohen, F]] | [[Category: Cohen, F]] | ||
[[Category: Neau, D | [[Category: Dozzo, P]] | ||
[[Category: Haglund, C M]] | |||
[[Category: Hilderbrandt, D J]] | |||
[[Category: Kane, T R]] | |||
[[Category: Linsell, M S]] | |||
[[Category: Machajewski, T]] | |||
[[Category: McEnroe, G]] | |||
[[Category: Neau, D B]] | |||
[[Category: Pakhomova, S]] | [[Category: Pakhomova, S]] | ||
[[Category: Pogliano, J]] | [[Category: Pogliano, J]] | ||
[[Category: Serio, A | [[Category: Serio, A W]] | ||
[[Category: | [[Category: Sharp, M]] | ||
[[Category: | [[Category: Waldrop, G L]] | ||
[[Category: | [[Category: Wlasichuk, K B]] | ||
[[Category: | [[Category: Atp grasp]] | ||
[[Category: | [[Category: Carboxylase]] | ||
[[Category: | [[Category: Inhibitor]] | ||
[[Category: | [[Category: Ligase]] | ||
Revision as of 09:26, 31 July 2019
Crystal Structure of Haemophilus Influenzae Biotin Carboxylase Complexed with 7-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2-chloro-6-(pyridin-3-yl)phenyl)pyrido[2,3-d]pyrimidin-2-amineCrystal Structure of Haemophilus Influenzae Biotin Carboxylase Complexed with 7-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2-chloro-6-(pyridin-3-yl)phenyl)pyrido[2,3-d]pyrimidin-2-amine
Structural highlights
Function[ACCC_HAEIN] This protein is a component of the acetyl coenzyme A carboxylase complex; first, biotin carboxylase catalyzes the carboxylation of the carrier protein and then the transcarboxylase transfers the carboxyl group to form malonyl-CoA. Publication Abstract from PubMedA major challenge for new antibiotic discovery is predicting the physicochemical properties that enable small molecules to permeate Gram-negative bacterial membranes. We have applied physicochemical lessons from previous work to redesign and improve the antibacterial potency of pyridopyrimidine inhibitors of biotin carboxylase (BC) by up to 64-fold and 16-fold against E. coli and P. aeruginosa, respectively. Antibacterial and enzyme potency assessments in the presence of an outer membrane permeabilizing agent or in efflux-compromised strains indicate that penetration and efflux properties of many redesigned BC inhibitors could be improved to various extents. Spontaneous resistance to the improved pyridopyrimidine inhibitors in P. aeruginosa occurs at very low frequencies between 10-8 to 10-9. However, resistant isolates had alarmingly high MIC shifts (16 to >128-fold) compared to the parent strain. Whole genome sequencing of resistant isolates revealed that either BC target mutations or efflux pump overexpression can lead to the development of high-level resistance. Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase.,Andrews LD, Kane TR, Dozzo P, Haglund CM, Hilderbrandt DJ, Linsell MS, Machajewski T, McEnroe G, Serio AW, Wlasichuk KB, Neau DB, Pakhomova S, Waldrop GL, Sharp M, Pogliano J, Cirz R, Cohen F J Med Chem. 2019 Jul 15. doi: 10.1021/acs.jmedchem.9b00625. PMID:31306011[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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