6nlm: Difference between revisions
New page: '''Unreleased structure''' The entry 6nlm is ON HOLD Authors: Lovell, S., Punchi-Hewage, A., Battaile, K.P., Yao, H., Nammalwar, B., Gnanasekaran, K.K., Bunce, R.A., Reitz, A.B., Rivera... |
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The | ==1.90 A resolution structure of WT BfrB from Pseudomonas aeruginosa in complex with a protein-protein interaction inhibitor (analog 15)== | ||
<StructureSection load='6nlm' size='340' side='right'caption='[[6nlm]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6nlm]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_PAO1 Pseudomonas aeruginosa PAO1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NLM 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FE2:FE+(II)+ION'>FE2</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=KT1:4-{[3-(4-hydroxy-2-methoxyphenyl)propyl]amino}-1H-isoindole-1,3(2H)-dione'>KT1</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</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=6nlm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nlm OCA], [https://pdbe.org/6nlm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nlm RCSB], [https://www.ebi.ac.uk/pdbsum/6nlm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nlm ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9HY79_PSEAE Q9HY79_PSEAE] Iron-storage protein (By similarity). Iron-storage protein, whose ferroxidase center binds Fe(2+) ions, oxidizes them by dioxygen to Fe(3+), and participates in the subsequent Fe(3+) oxide mineral core formation within the central cavity of the protein complex (By similarity).[PIRNR:PIRNR002560] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The iron storage protein bacterioferritin (BfrB) is central to bacterial iron homeostasis. The mobilization of iron from BfrB, which requires binding by a cognate ferredoxin (Bfd), is essential to the regulation of cytosolic iron levels in P. aeruginosa. This paper describes the structure-guided development of small molecule inhibitors of the BfrB-Bfd protein-protein interaction. The process was initiated by screening a fragment library and followed by obtaining the structure of a fragment hit bound to BfrB. The structural insights were used to develop a series of 4-(benzylamino)- and 4-((3-phenylpropyl)amino)-isoindoline-1,3-dione analogs that selectively bind BfrB at the Bfd binding site. Challenging P. aeruginosa cells with the 4-substituted isoindoline analogs revealed a dose-dependent growth phenotype. Further investigation determined that the analogs elicit a pyoverdin hyperproduction phenotype that is consistent with blockade of the BfrB-Bfd interaction and ensuing irreversible accumulation of iron in BfrB, with concomitant depletion of iron in the cytosol. The irreversible accumulation of iron in BfrB prompted by the 4-substituted isoindoline analogs was confirmed by visualization of BfrB-iron in P. aeruginosa cell lysates separated on native PAGE gels and stained for iron with Ferene S. Challenging P. aeruginosa cultures with a combination of commercial fluoroquinolone and our isoindoline analogs results in significantly lower cell survival relative to treatment with either antibiotic or analog alone. Collectively, these findings furnish proof of concept for the usefulness of small molecule probes designed to dysregulate bacterial iron homeostasis by targeting a protein-protein interaction pivotal for iron storage in the bacterial cell. | |||
Small Molecule Inhibitors of the BfrB-Bfd Interaction Decrease Pseudomonas aeruginosa Fitness and Potentiate Fluoroquinolone Activity.,Punchi Hewage AND, Yao H, Nammalwar B, Gnanasekaran KK, Lovell S, Bunce RA, Eshelman K, Phaniraj SM, Lee MM, Peterson BR, Battaile KP, Reitz AB, Rivera M J Am Chem Soc. 2019 May 9. doi: 10.1021/jacs.9b00394. PMID:31038945<ref>PMID:31038945</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6nlm" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: | ==See Also== | ||
[[Category: | *[[Ferritin 3D structures|Ferritin 3D structures]] | ||
[[Category: Lovell | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Pseudomonas aeruginosa PAO1]] | |||
[[Category: Battaile KP]] | |||
[[Category: Bunce RA]] | |||
[[Category: Gnanasekaran KK]] | |||
[[Category: Lovell S]] | |||
[[Category: Nammalwar B]] | |||
[[Category: Punchi-Hewage A]] | |||
[[Category: Reitz AB]] | |||
[[Category: Rivera M]] | |||
[[Category: Yao H]] | |||