7a8p: Difference between revisions

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<StructureSection load='7a8p' size='340' side='right'caption='[[7a8p]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
<StructureSection load='7a8p' size='340' side='right'caption='[[7a8p]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7a8p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A8P OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7A8P FirstGlance]. <br>
<table><tr><td colspan='2'>[[7a8p]] is a 1 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=7A8P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A8P FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R4Q:(3~{R})-1-[(2~{R})-2-[4-(2-chloranyl-4-fluoranyl-phenyl)-2-oxidanylidene-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic+acid'>R4Q</scene></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]] 3.5&#8491;</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA-directed_RNA_polymerase DNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.6 2.7.7.6] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R4Q:(3~{R})-1-[(2~{R})-2-[4-(2-chloranyl-4-fluoranyl-phenyl)-2-oxidanylidene-chromen-7-yl]oxypropanoyl]piperidine-3-carboxylic+acid'>R4Q</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7a8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a8p OCA], [http://pdbe.org/7a8p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7a8p RCSB], [http://www.ebi.ac.uk/pdbsum/7a8p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7a8p ProSAT]</span></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=7a8p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a8p OCA], [https://pdbe.org/7a8p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a8p RCSB], [https://www.ebi.ac.uk/pdbsum/7a8p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a8p ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/RPOM_HUMAN RPOM_HUMAN]] DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates.<ref>PMID:21278163</ref>
[https://www.uniprot.org/uniprot/RPOM_HUMAN RPOM_HUMAN] DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates.<ref>PMID:21278163</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system(1-6). The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS(7-17), and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease.


Small-molecule inhibitors of human mitochondrial DNA transcription.,Bonekamp NA, Peter B, Hillen HS, Felser A, Bergbrede T, Choidas A, Horn M, Unger A, Di Lucrezia R, Atanassov I, Li X, Koch U, Menninger S, Boros J, Habenberger P, Giavalisco P, Cramer P, Denzel MS, Nussbaumer P, Klebl B, Falkenberg M, Gustafsson CM, Larsson NG Nature. 2020 Dec;588(7839):712-716. doi: 10.1038/s41586-020-03048-z. Epub 2020, Dec 16. PMID:33328633<ref>PMID:33328633</ref>
==See Also==
 
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7a8p" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: DNA-directed RNA polymerase]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Atanassov, I]]
[[Category: Atanassov I]]
[[Category: Bergbrede, T]]
[[Category: Bergbrede T]]
[[Category: Bonekamp, N]]
[[Category: Bonekamp N]]
[[Category: Boros, J]]
[[Category: Boros J]]
[[Category: Choidas, A]]
[[Category: Choidas A]]
[[Category: Cramer, P]]
[[Category: Cramer P]]
[[Category: Denzel, M]]
[[Category: Denzel M]]
[[Category: Falkenberg, M]]
[[Category: Falkenberg M]]
[[Category: Felser, A]]
[[Category: Felser A]]
[[Category: Giavalisco, P]]
[[Category: Giavalisco P]]
[[Category: Gustafsson, C M]]
[[Category: Gustafsson CM]]
[[Category: Habenberger, P]]
[[Category: Habenberger P]]
[[Category: Hillen, H S]]
[[Category: Hillen HS]]
[[Category: Horn, M]]
[[Category: Horn M]]
[[Category: Klebl, B]]
[[Category: Klebl B]]
[[Category: Koch, U]]
[[Category: Koch U]]
[[Category: Larsson, N G]]
[[Category: Larsson NG]]
[[Category: Li, X]]
[[Category: Li X]]
[[Category: Lucrezia, R di]]
[[Category: Menninger S]]
[[Category: Menninger, S]]
[[Category: Nussbaumer P]]
[[Category: Nussbaumer, P]]
[[Category: Peter B]]
[[Category: Peter, B]]
[[Category: Unger A]]
[[Category: Unger, A]]
[[Category: Di Lucrezia R]]
[[Category: Inhibitor]]
[[Category: Mitochondria]]
[[Category: Polymerase]]
[[Category: Transcription]]

Latest revision as of 10:43, 1 May 2024

Structure of human mitochondrial RNA polymerase in complex with IMT inhibitor.Structure of human mitochondrial RNA polymerase in complex with IMT inhibitor.

Structural highlights

7a8p is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.5Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RPOM_HUMAN DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates.[1]

See Also

References

  1. ↑ Minczuk M, He J, Duch AM, Ettema TJ, Chlebowski A, Dzionek K, Nijtmans LG, Huynen MA, Holt IJ. TEFM (c17orf42) is necessary for transcription of human mtDNA. Nucleic Acids Res. 2011 May;39(10):4284-99. doi: 10.1093/nar/gkq1224. Epub 2011, Jan 28. PMID:21278163 doi:10.1093/nar/gkq1224

7a8p, resolution 3.50Å

Drag the structure with the mouse to rotate

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OCA
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