7t3h: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7t3h]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Photorhabdus_australis Photorhabdus australis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T3H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T3H FirstGlance]. <br> | <table><tr><td colspan='2'>[[7t3h]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Photorhabdus_australis Photorhabdus australis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T3H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T3H 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=7t3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t3h OCA], [https://pdbe.org/7t3h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t3h RCSB], [https://www.ebi.ac.uk/pdbsum/7t3h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t3h ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron crystallography, [[Resolution|Resolution]] 1.05Å</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=7t3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t3h OCA], [https://pdbe.org/7t3h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t3h RCSB], [https://www.ebi.ac.uk/pdbsum/7t3h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t3h ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/A0A1C0U7H2_9GAMM A0A1C0U7H2_9GAMM] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Discovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its beta-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development. | Discovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its beta-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development. | ||
Computational identification of a systemic antibiotic for gram-negative bacteria.,Miller RD, Iinishi A, Modaresi SM, Yoo BK, Curtis TD, Lariviere PJ, Liang L, Son S, Nicolau S, Bargabos R, Morrissette M, Gates MF, Pitt N, Jakob RP, Rath P, Maier T, Malyutin AG, Kaiser JT, Niles S, Karavas B, Ghiglieri M, Bowman SEJ, Rees DC, Hiller S, Lewis K Nat Microbiol. 2022 Oct;7(10):1661-1672. doi: 10.1038/s41564-022-01227-4. Epub, 2022 Sep 26. PMID:36163500<ref>PMID:36163500</ref> | Computational identification of a systemic antibiotic for gram-negative bacteria.,Miller RD, Iinishi A, Modaresi SM, Yoo BK, Curtis TD, Lariviere PJ, Liang L, Son S, Nicolau S, Bargabos R, Morrissette M, Gates MF, Pitt N, Jakob RP, Rath P, Maier T, Malyutin AG, Kaiser JT, Niles S, Karavas B, Ghiglieri M, Bowman SEJ, Rees DC, Hiller S, Lewis K Nat Microbiol. 2022 Oct;7(10):1661-1672. doi: 10.1038/s41564-022-01227-4. Epub , 2022 Sep 26. PMID:36163500<ref>PMID:36163500</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Latest revision as of 09:47, 21 November 2024
MicroED structure of DynobactinMicroED structure of Dynobactin
Structural highlights
FunctionPublication Abstract from PubMedDiscovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its beta-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development. Computational identification of a systemic antibiotic for gram-negative bacteria.,Miller RD, Iinishi A, Modaresi SM, Yoo BK, Curtis TD, Lariviere PJ, Liang L, Son S, Nicolau S, Bargabos R, Morrissette M, Gates MF, Pitt N, Jakob RP, Rath P, Maier T, Malyutin AG, Kaiser JT, Niles S, Karavas B, Ghiglieri M, Bowman SEJ, Rees DC, Hiller S, Lewis K Nat Microbiol. 2022 Oct;7(10):1661-1672. doi: 10.1038/s41564-022-01227-4. Epub , 2022 Sep 26. PMID:36163500[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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