8bbk: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 8bbk is ~~ON HOLD until Paper~~ Publication

==Crystal structure of human Sirt3 in complex with a fragment of the human AROS protein==

== Structural highlights ==

<table><tr><td colspan='2'>[[8bbk]] is a 12 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=8BBK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BBK FirstGlance]. <br>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.27Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8bbk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bbk OCA], [https://pdbe.org/8bbk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bbk RCSB], [https://www.ebi.ac.uk/pdbsum/8bbk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bbk ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>

== Publication Abstract from PubMed ==

The protein lysine deacylases of the NAD(+)-dependent Sirtuin family contribute to metabolic regulation, stress responses, and aging processes, and the human Sirtuin isoforms, Sirt1-7, are considered drug targets for aging-related diseases. The nuclear isoform Sirt1 deacetylates histones and transcription factors to regulate, e.g., metabolic adaptations and circadian mechanisms, and it is used as a therapeutic target for Huntington's disease and psoriasis. Sirt1 is regulated through a multitude of mechanisms, including the interaction with regulatory proteins such as the inhibitors Tat and Dbc1 or the activator AROS. Here, we describe a molecular characterization of AROS and how it regulates Sirt1. We find that AROS is a partly intrinsically disordered protein (IDP) that inhibits rather than activates Sirt1. A biochemical characterization of the interaction including binding and stability assays, NMR spectroscopy, mass spectrometry, and a crystal structure of Sirtuin/AROS peptide complex reveal that AROS acts as a competitive inhibitor, through binding to the Sirt1 substrate peptide site. Our results provide molecular insights in the physiological regulation of Sirt1 by a regulator protein and suggest the peptide site as an opportunity for Sirt1-targeted drug development.

~~Authors~~:

Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein.,Weiss S, Adolph RS, Schweimer K, DiFonzo A, Meleshin M, Schutkowski M, Steegborn C Int J Mol Sci. 2022 Oct 23;23(21):12764. doi: 10.3390/ijms232112764. PMID:36361557<ref>PMID:36361557</ref>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Steegborn C]]

[[Category: Weiss S]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8bbk is ON HOLD  until Paper Publication
+==Crystal structure of human Sirt3 in complex with a fragment of the human AROS protein==
+<StructureSection load='8bbk' size='340' side='right'caption='[[8bbk]], [[Resolution|resolution]] 3.27&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8bbk]] is a 12 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=8BBK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BBK FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.27&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8bbk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bbk OCA], [https://pdbe.org/8bbk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bbk RCSB], [https://www.ebi.ac.uk/pdbsum/8bbk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bbk ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/SIR3_HUMAN SIR3_HUMAN] NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.<ref>PMID:16788062</ref> <ref>PMID:18680753</ref> <ref>PMID:18794531</ref> <ref>PMID:19535340</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The protein lysine deacylases of the NAD(+)-dependent Sirtuin family contribute to metabolic regulation, stress responses, and aging processes, and the human Sirtuin isoforms, Sirt1-7, are considered drug targets for aging-related diseases. The nuclear isoform Sirt1 deacetylates histones and transcription factors to regulate, e.g., metabolic adaptations and circadian mechanisms, and it is used as a therapeutic target for Huntington's disease and psoriasis. Sirt1 is regulated through a multitude of mechanisms, including the interaction with regulatory proteins such as the inhibitors Tat and Dbc1 or the activator AROS. Here, we describe a molecular characterization of AROS and how it regulates Sirt1. We find that AROS is a partly intrinsically disordered protein (IDP) that inhibits rather than activates Sirt1. A biochemical characterization of the interaction including binding and stability assays, NMR spectroscopy, mass spectrometry, and a crystal structure of Sirtuin/AROS peptide complex reveal that AROS acts as a competitive inhibitor, through binding to the Sirt1 substrate peptide site. Our results provide molecular insights in the physiological regulation of Sirt1 by a regulator protein and suggest the peptide site as an opportunity for Sirt1-targeted drug development.
-Authors:
+Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein.,Weiss S, Adolph RS, Schweimer K, DiFonzo A, Meleshin M, Schutkowski M, Steegborn C Int J Mol Sci. 2022 Oct 23;23(21):12764. doi: 10.3390/ijms232112764. PMID:36361557<ref>PMID:36361557</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8bbk" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Steegborn C]]
+[[Category: Weiss S]]