2h2i: Difference between revisions
New page: left|200px<br /><applet load="2h2i" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h2i, resolution 1.80Å" /> '''The Structural basis... |
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[[Image:2h2i.gif|left|200px]]<br /><applet load="2h2i" size=" | [[Image:2h2i.gif|left|200px]]<br /><applet load="2h2i" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2h2i, resolution 1.80Å" /> | caption="2h2i, resolution 1.80Å" /> | ||
'''The Structural basis of Sirtuin Substrate Affinity'''<br /> | '''The Structural basis of Sirtuin Substrate Affinity'''<br /> | ||
==Overview== | ==Overview== | ||
Sirtuins comprise a family of enzymes that catalyze the deacetylation of | Sirtuins comprise a family of enzymes that catalyze the deacetylation of acetyllysine side chains in a reaction that consumes NAD+. Although several crystal structures of sirtuins bound to non-native acetyl peptides have been determined, relatively little about how sirtuins discriminate among different substrates is understood. We have carried out a systematic structural and thermodynamic analysis of several peptides bound to a single sirtuin, the Sir2 homologue from Thermatoga maritima (Sir2Tm). We report structures of five different forms of Sir2Tm: two forms bound to the p53 C-terminal tail in the acetylated and unacetylated states, two forms bound to putative acetyl peptide substrates derived from the structured domains of histones H3 and H4, and one form bound to polypropylene glycol (PPG), which resembles the apoenzyme. The structures reveal previously unobserved complementary side chain interactions between Sir2Tm and the first residue N-terminal to the acetyllysine (position -1) and the second residue C-terminal to the acetyllysine (position +2). Isothermal titration calorimetry was used to compare binding constants between wild-type and mutant forms of Sir2Tm and between additional acetyl peptide substrates with substitutions at positions -1 and +2. The results are consistent with a model in which peptide positions -1 and +2 play a significant role in sirtuin substrate binding. This model provides a framework for identifying sirtuin substrates. | ||
==About this Structure== | ==About this Structure== | ||
2H2I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Thermotoga_maritima Thermotoga maritima] with ZN and ZPG as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | 2H2I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Thermotoga_maritima Thermotoga maritima] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=ZPG:'>ZPG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H2I OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Thermotoga maritima]] | [[Category: Thermotoga maritima]] | ||
[[Category: Cosgrove, M | [[Category: Cosgrove, M S.]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
[[Category: ZPG]] | [[Category: ZPG]] | ||
[[Category: sir2tm-ppg]] | [[Category: sir2tm-ppg]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:37:39 2008'' | ||
Revision as of 18:37, 21 February 2008
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The Structural basis of Sirtuin Substrate Affinity
OverviewOverview
Sirtuins comprise a family of enzymes that catalyze the deacetylation of acetyllysine side chains in a reaction that consumes NAD+. Although several crystal structures of sirtuins bound to non-native acetyl peptides have been determined, relatively little about how sirtuins discriminate among different substrates is understood. We have carried out a systematic structural and thermodynamic analysis of several peptides bound to a single sirtuin, the Sir2 homologue from Thermatoga maritima (Sir2Tm). We report structures of five different forms of Sir2Tm: two forms bound to the p53 C-terminal tail in the acetylated and unacetylated states, two forms bound to putative acetyl peptide substrates derived from the structured domains of histones H3 and H4, and one form bound to polypropylene glycol (PPG), which resembles the apoenzyme. The structures reveal previously unobserved complementary side chain interactions between Sir2Tm and the first residue N-terminal to the acetyllysine (position -1) and the second residue C-terminal to the acetyllysine (position +2). Isothermal titration calorimetry was used to compare binding constants between wild-type and mutant forms of Sir2Tm and between additional acetyl peptide substrates with substitutions at positions -1 and +2. The results are consistent with a model in which peptide positions -1 and +2 play a significant role in sirtuin substrate binding. This model provides a framework for identifying sirtuin substrates.
About this StructureAbout this Structure
2H2I is a Single protein structure of sequence from Thermotoga maritima with and as ligands. Full crystallographic information is available from OCA.
ReferenceReference
The structural basis of sirtuin substrate affinity., Cosgrove MS, Bever K, Avalos JL, Muhammad S, Zhang X, Wolberger C, Biochemistry. 2006 Jun 20;45(24):7511-21. PMID:16768447
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