8ki3: Difference between revisions
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The | ==Structure of the human ATP synthase bound to bedaquiline (composite)== | ||
<StructureSection load='8ki3' size='340' side='right'caption='[[8ki3]], [[Resolution|resolution]] 2.89Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ki3]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8KI3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8KI3 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]] 2.89Å</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=8ki3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ki3 OCA], [https://pdbe.org/8ki3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ki3 RCSB], [https://www.ebi.ac.uk/pdbsum/8ki3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ki3 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ATP5H_HUMAN ATP5H_HUMAN] Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements. | |||
<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 8ki3" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Gong H]] | |||
[[Category: Lai Y]] | |||
[[Category: Zhang Y]] | |||
Latest revision as of 16:14, 21 August 2024
Structure of the human ATP synthase bound to bedaquiline (composite)Structure of the human ATP synthase bound to bedaquiline (composite)
Structural highlights
FunctionATP5H_HUMAN Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(0) domain and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements. 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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