8j0s: Difference between revisions
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==Cryo-EM structure of Mycobacterium tuberculosis ATP synthase in complex with bedaquiline(BDQ)== | |||
<StructureSection load='8j0s' size='340' side='right'caption='[[8j0s]], [[Resolution|resolution]] 2.58Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8j0s]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8J0S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8J0S FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.58Å</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=8j0s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8j0s OCA], [https://pdbe.org/8j0s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8j0s RCSB], [https://www.ebi.ac.uk/pdbsum/8j0s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8j0s ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ATP6_MYCTU ATP6_MYCTU] Key component of the proton channel; it plays a direct role in the translocation of protons across the membrane. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase(1,2). However, BDQ also inhibits human ATP synthase(3). At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs. | |||
Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.,Zhang Y, Lai Y, Zhou S, Ran T, Zhang Y, Zhao Z, Feng Z, Yu L, Xu J, Shi K, Wang J, Pang Y, Li L, Chen H, Guddat LW, Gao Y, Liu F, Rao Z, Gong H Nature. 2024 Jul;631(8020):409-414. doi: 10.1038/s41586-024-07605-8. Epub 2024 , Jul 3. PMID:38961288<ref>PMID:38961288</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Gong | <div class="pdbe-citations 8j0s" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: Liu | <references/> | ||
[[Category: Rao | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | |||
[[Category: Gong H]] | |||
[[Category: Lai Y]] | |||
[[Category: Liu F]] | |||
[[Category: Rao Z]] | |||
[[Category: Zhang Y]] | |||
Latest revision as of 16:13, 21 August 2024
Cryo-EM structure of Mycobacterium tuberculosis ATP synthase in complex with bedaquiline(BDQ)Cryo-EM structure of Mycobacterium tuberculosis ATP synthase in complex with bedaquiline(BDQ)
Structural highlights
FunctionATP6_MYCTU Key component of the proton channel; it plays a direct role in the translocation of protons across the membrane. Publication Abstract from PubMedBedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase(1,2). However, BDQ also inhibits human ATP synthase(3). At present, how these compounds interact with either M. tuberculosis ATP synthase or human ATP synthase is unclear. Here we present cryogenic electron microscopy structures of M. tuberculosis ATP synthase with and without BDQ and TBAJ-587 bound, and human ATP synthase bound to BDQ. The two inhibitors interact with subunit a and the c-ring at the leading site, c-only sites and lagging site in M. tuberculosis ATP synthase, showing that BDQ and TBAJ-587 have similar modes of action. The quinolinyl and dimethylamino units of the compounds make extensive contacts with the protein. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs. Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587.,Zhang Y, Lai Y, Zhou S, Ran T, Zhang Y, Zhao Z, Feng Z, Yu L, Xu J, Shi K, Wang J, Pang Y, Li L, Chen H, Guddat LW, Gao Y, Liu F, Rao Z, Gong H Nature. 2024 Jul;631(8020):409-414. doi: 10.1038/s41586-024-07605-8. Epub 2024 , Jul 3. PMID:38961288[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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