6oi8: Difference between revisions

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-'''Unreleased structure'''
-The entry 6oi8 is ON HOLD  until Paper Publication
+==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]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6oi8]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_influenzae_Rd_KW20 Haemophilus influenzae Rd KW20]. 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 [https://proteopedia.org/fgij/fg.htm?mol=6OI8 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</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=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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6oi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oi8 OCA], [https://pdbe.org/6oi8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oi8 RCSB], [https://www.ebi.ac.uk/pdbsum/6oi8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oi8 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://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 &gt;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.
-Authors: Andrews, L.D., Kane, T.R., Dozzo, P., Haglund, C.M., Hilderbrandt, D.J., Linsell, M.S., Machajewski, T., McEnroe, G., Serio, A.W., Wlasichuk, K.B., Neau, D.B., Pakhomova, S., Waldrop, G.L., Sharp, M., Pogliano, J., Cirz, R., Cohen, F.
+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>
-Description: 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
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Machajewski, T]]
+<div class="pdbe-citations 6oi8" style="background-color:#fffaf0;"></div>
-[[Category: Cirz, R]]
-[[Category: Sharp, M]]
+==See Also==
-[[Category: Cohen, F]]
+*[[Acetyl-CoA carboxylase 3D structures|Acetyl-CoA carboxylase 3D structures]]
-[[Category: Neau, D.B]]
+== References ==
-[[Category: Pakhomova, S]]
+<references/>
-[[Category: Haglund, C.M]]
+__TOC__
-[[Category: Kane, T.R]]
+</StructureSection>
-[[Category: Pogliano, J]]
+[[Category: Haemophilus influenzae Rd KW20]]
-[[Category: Serio, A.W]]
+[[Category: Large Structures]]
-[[Category: Dozzo, P]]
+[[Category: Andrews LD]]
-[[Category: Mcenroe, G]]
+[[Category: Cirz R]]
-[[Category: Waldrop, G.L]]
+[[Category: Cohen F]]
-[[Category: Linsell, M.S]]
+[[Category: Dozzo P]]
-[[Category: Andrews, L.D]]
+[[Category: Haglund CM]]
-[[Category: Hilderbrandt, D.J]]
+[[Category: Hilderbrandt DJ]]
-[[Category: Wlasichuk, K.B]]
+[[Category: Kane TR]]
+[[Category: Linsell MS]]
+[[Category: Machajewski T]]
+[[Category: McEnroe G]]
+[[Category: Neau DB]]
+[[Category: Pakhomova S]]
+[[Category: Pogliano J]]
+[[Category: Serio AW]]
+[[Category: Sharp M]]
+[[Category: Waldrop GL]]
+[[Category: Wlasichuk KB]]