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6oi9

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Revision as of 12:01, 18 December 2019

Crystal Structure of E. coli Biotin Carboxylase Complexed with 7-[3-(aminomethyl)pyrrolidin-1-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine

Structural highlights

6oi9 is a 2 chain structure with sequence from Escherichia coli umnk88. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	accC, UMNK88_4016 (Escherichia coli UMNK88)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[A0A0E0U408_ECOLX] 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.[RuleBase:RU365063]

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Optimization and Mechanistic Characterization of Pyridopyrimidine Inhibitors of Bacterial Biotin Carboxylase. J Med Chem. 2019 Jul 15. doi: 10.1021/acs.jmedchem.9b00625. PMID:31306011 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00625

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6oi9"

@@ Line 3: / Line 3: @@
 <StructureSection load='6oi9' size='340' side='right'caption='[[6oi9]], [[Resolution|resolution]] 2.06&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6oi9]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OI9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OI9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6oi9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Escherichia_coli_umnk88 Escherichia coli umnk88]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OI9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OI9 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=MQM:7-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine'>MQM</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">accC, UMNK88_4016 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=696406 Escherichia coli UMNK88])</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=6oi9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oi9 OCA], [http://pdbe.org/6oi9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oi9 RCSB], [http://www.ebi.ac.uk/pdbsum/6oi9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oi9 ProSAT]</span></td></tr>
 </table>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Escherichia coli umnk88]]
 [[Category: Large Structures]]
 [[Category: Andrews, L D]]

6oi9

From Proteopedia

Revision as of 12:01, 18 December 2019

Crystal Structure of E. coli Biotin Carboxylase Complexed with 7-[3-(aminomethyl)pyrrolidin-1-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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