7liw
From Proteopedia
(Difference between revisions)
| (2 intermediate revisions not shown.) | |||
| Line 3: | Line 3: | ||
<StructureSection load='7liw' size='340' side='right'caption='[[7liw]], [[Resolution|resolution]] 2.85Å' scene=''> | <StructureSection load='7liw' size='340' side='right'caption='[[7liw]], [[Resolution|resolution]] 2.85Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'> | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LIW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LIW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=Y2A:(2S)-2-hydroxy-2-[2-oxo-2-(phosphonooxy)ethyl]butanedioic+acid'>Y2A</scene | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.85Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene>, <scene name='pdbligand=Y2A:(2S)-2-hydroxy-2-[2-oxo-2-(phosphonooxy)ethyl]butanedioic+acid'>Y2A</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=7liw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7liw OCA], [https://pdbe.org/7liw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7liw RCSB], [https://www.ebi.ac.uk/pdbsum/7liw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7liw 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=7liw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7liw OCA], [https://pdbe.org/7liw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7liw RCSB], [https://www.ebi.ac.uk/pdbsum/7liw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7liw ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == Function == | ||
| - | [[https://www.uniprot.org/uniprot/ACLY_HUMAN ACLY_HUMAN]] ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.<ref>PMID:23932781</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo-EM structures of human ACLY, alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH-ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho-citryl-CoA intermediate in the ASH domain. ACLY with acetyl-CoA and oxaloacetate products shows the products bound in the ASH domain, with an additional oxaloacetate in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY-associated metabolic disorders. | ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo-EM structures of human ACLY, alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH-ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho-citryl-CoA intermediate in the ASH domain. ACLY with acetyl-CoA and oxaloacetate products shows the products bound in the ASH domain, with an additional oxaloacetate in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY-associated metabolic disorders. | ||
| - | + | , PMID:31873304<ref>PMID:31873304</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> | ||
</div> | </div> | ||
<div class="pdbe-citations 7liw" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7liw" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[ATP-citrate synthase 3D structures|ATP-citrate synthase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: ATP citrate synthase]] | ||
| - | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Marmorstein | + | [[Category: Marmorstein R]] |
| - | [[Category: Wei | + | [[Category: Wei X]] |
| - | + | ||
Current revision
Local refinement of human ATP citrate lyase E599Q mutant ASH domain
| |||||||||||
