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==== | ==Mycobacterial CIII2CIV2 supercomplex, inhibitor free, -Lpqe cyt cc open== | ||
<StructureSection load='7rh6' size='340' side='right'caption='[[7rh6]]' scene=''> | <StructureSection load='7rh6' size='340' side='right'caption='[[7rh6]], [[Resolution|resolution]] 3.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7rh6]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis_MC2_155 Mycolicibacterium smegmatis MC2 155]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RH6 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=7rh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rh6 OCA], [https://pdbe.org/7rh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rh6 RCSB], [https://www.ebi.ac.uk/pdbsum/7rh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rh6 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9XX:(2S)-1-(hexadecanoyloxy)propan-2-yl+(10S)-10-methyloctadecanoate'>9XX</scene>, <scene name='pdbligand=9Y0:[(2~{R})-3-[2-azanylethoxy(oxidanyl)phosphoryl]oxy-2-hexadecanoyloxy-propyl]+(~{Z})-octadec-9-enoate'>9Y0</scene>, <scene name='pdbligand=9YF:(2R)-2-(hexadecanoyloxy)-3-{[(S)-hydroxy{[(1R,2R,3R,4R,5R,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}propyl+(9S)-9-methyloctadecanoate'>9YF</scene>, <scene name='pdbligand=CDL:CARDIOLIPIN'>CDL</scene>, <scene name='pdbligand=CU:COPPER+(II)+ION'>CU</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=HEA:HEME-A'>HEA</scene>, <scene name='pdbligand=HEC:HEME+C'>HEC</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=MQ9:MENAQUINONE-9'>MQ9</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</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=7rh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rh6 OCA], [https://pdbe.org/7rh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rh6 RCSB], [https://www.ebi.ac.uk/pdbsum/7rh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rh6 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/I7FPH1_MYCS2 I7FPH1_MYCS2] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than 50 years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII(2)CIV(2)). In mycobacterial electron transport chains, CIII(2)CIV(2) replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII(2)CIV(2) at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII(2)CIV(2) both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII(2)CIV(2) activity. | |||
Structure of mycobacterial CIII(2)CIV(2) respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203).,Yanofsky DJ, Di Trani JM, Krol S, Abdelaziz R, Bueler SA, Imming P, Brzezinski P, Rubinstein JL Elife. 2021 Sep 30;10:e71959. doi: 10.7554/eLife.71959. PMID:34590581<ref>PMID:34590581</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7rh6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Cytochrome bc1 3D structures|Cytochrome bc1 3D structures]] | |||
*[[Cytochrome c oxidase 3D structures|Cytochrome c oxidase 3D structures]] | |||
*[[Superoxide dismutase 3D structures|Superoxide dismutase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycolicibacterium smegmatis MC2 155]] | ||
[[Category: Di Trani JM]] | |||
[[Category: Rubinstein JL]] | |||
[[Category: Yanofsky DJ]] | |||
Latest revision as of 16:58, 6 November 2024
Mycobacterial CIII2CIV2 supercomplex, inhibitor free, -Lpqe cyt cc openMycobacterial CIII2CIV2 supercomplex, inhibitor free, -Lpqe cyt cc open
Structural highlights
FunctionPublication Abstract from PubMedThe imidazopyridine telacebec, also known as Q203, is one of only a few new classes of compounds in more than 50 years with demonstrated antituberculosis activity in humans. Telacebec inhibits the mycobacterial respiratory supercomplex composed of complexes III and IV (CIII(2)CIV(2)). In mycobacterial electron transport chains, CIII(2)CIV(2) replaces canonical CIII and CIV, transferring electrons from the intermediate carrier menaquinol to the final acceptor, molecular oxygen, while simultaneously transferring protons across the inner membrane to power ATP synthesis. We show that telacebec inhibits the menaquinol:oxygen oxidoreductase activity of purified Mycobacterium smegmatis CIII(2)CIV(2) at concentrations similar to those needed to inhibit electron transfer in mycobacterial membranes and Mycobacterium tuberculosis growth in culture. We then used electron cryomicroscopy (cryoEM) to determine structures of CIII(2)CIV(2) both in the presence and absence of telacebec. The structures suggest that telacebec prevents menaquinol oxidation by blocking two different menaquinol binding modes to prevent CIII(2)CIV(2) activity. Structure of mycobacterial CIII(2)CIV(2) respiratory supercomplex bound to the tuberculosis drug candidate telacebec (Q203).,Yanofsky DJ, Di Trani JM, Krol S, Abdelaziz R, Bueler SA, Imming P, Brzezinski P, Rubinstein JL Elife. 2021 Sep 30;10:e71959. doi: 10.7554/eLife.71959. PMID:34590581[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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