Journal:JBIC:1

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[[Image: 3dzy2.png|420px|left|thumb| Human PPARγ bound to RXRα and PPRE DNA strand, [[3dzy]]]]
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<StructureSection load="" size="400" color="" frame="true" spin="on" Scene ="Journal:JBIC:1/Jbic1_opening/2" side="right" caption="Crystal structure of cobalt bound adenylate kinase from ''Desulfovibrio gigas''">
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{{STRUCTURE_3dzy| right| PDB=3dzy | SCENE=Peroxisome_Proliferator-Activated_Receptors/Ppar_opening4/1 |CAPTION= Crystal Structure of Human PPARγ, [[3dzy]] }}
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===Crystal structure of the zinc, cobalt and iron containing adenylate kinase from ''Desulfovibrio gigas'': a novel metal containing adenylate kinase from Gram-negative bacteria===
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The [[Peroxisome Proliferator-Activated Receptors]] (PPAR) α, δ, and γ are members of the nuclear receptor family. Since their discovery in the early 90s, it has become clear that the PPARs are essential modulators of environmental and dietary stimuli, acting as transcription factors to regulate mammalian metabolism, cellular differentiation, and tumorigenesis. The PPARs are the targets of numerous pharmaceutical drugs aimed at treating [http://en.wikipedia.org/wiki/Hyperlipidemia hypolipidemia] and [http://en.wikipedia.org/wiki/Diabetes diabetes] among other diseases.<ref>PMID:15860251</ref>
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<big>A. Mukhopadhyay, A.V. Kladova, S.A. Bursakov, O. Yu. Gavel, J.J. Calvete, V.L. Shnyrov, I. Moura, J.J.G. Moura, M.J. Romão, J. Trincão
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</big> <ref >DOI 10.1007/s00775-010-0700-8</ref>
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<hr/>
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<b>Molecular Tour</b><br>
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Adenylate kinase (ATP:AMP phosphotransferase, [[EC Number|EC]] 2.7.4.3; AK) is an essential catalyst for cellular growth and multiplication. AK belongs to a family of enzymes essential to life, and is highly abundant inside the cell. It is involved in the reversible transfer of the terminal phosphate group from Mg2+ATP to Mg2+AMP with high energy turnover: Mg2+ATP + AMP&#8596;Mg2+ADP + ADP.
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Adenylate kinases (AK) from Gram-negative bacteria are generally devoid of metal ions in their LID domain. However, <scene name='Journal:JBIC:1/Metal_bound/4'>three metal ions</scene>, zinc, cobalt and iron, have been found in AK from Gram-negative bacteria. Crystal structures of substrate-free AK from ''Desulfovibrio gigas'' with three different metal ions: <scene name='Journal:JBIC:1/Zinc_bound/3'>Zn2+, Zn-AK</scene> ([[2xb4]]); <scene name='Journal:JBIC:1/Cobalt_bound/7'>Co2+, Co-AK</scene> ([[3l0s]]) and <scene name='Journal:JBIC:1/Fe_bound/8'>Fe2+, Fe-AK</scene> ([[3l0p]]) bound in its LID domain have been determined by X-ray crystallography. All three crystal structures are very similar to each other with the same LID domain topology, the only change being the presence of the different metal atoms.<br />
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&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The structures of Zn- , Co- and Fe-AK contain the <scene name='Journal:JBIC:1/Lid_domain/5'>characteristic LID domain (residues 125-163)</scene> and <scene name='Journal:JBIC:1/Core_domain/1'>Core (residues 1-124 and 164-223) domains</scene>, which also include the AMP binding region. The LID domain harbors the <scene name='Journal:JBIC:1/Metal_motif/1'>Cys129-X5-His135-X15-Cys151-X2-Cys154- motif</scene>, which is responsible for metal binding in a tetrahedral fashion. In the absence of any substrate, the LID domain of all holo forms of AK was present in a fully open conformational state. The Core domain is <scene name='Journal:JBIC:1/Core_connection/3'>connected to the LID by residues 116-123 and 165-173</scene>. This Core domain mainly consists of a <scene name='Journal:JBIC:1/Core_helix/3'>five stranded beta sheet surrounded by 5 helices</scene> that keep the integrity of the tertiary structure of the enzyme. A <scene name='Journal:JBIC:1/Walker/4'>Walker motif</scene> with conserved sequence; <span style="color:#FF0000">G</span>-<span style="color:#FF8040">X</span>-<span style="color:#FFFF00">X</span>-<span style="color:#00FF00">G</span>-<span style="color:#0000FF">X</span>-<span style="color:#FF00FF">G</span>-<span style="color:#00FFFF">K</span> is present in the N-terminal region. The structures presented herein further reinforce the notion that the metal ion is purely structural, contributing to the stability of the LID domain.
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{{TOC limit|limit=2}}
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'''PDB references:''' Crystal structure of zinc containing Adenylate kinase from ''Desulfovibrio gigas'', [[2xb4]]; Crystal structure of Iron containing Adenylate kinase from ''Desulfovibrio gigas'' [[3l0p]]; Crystal structure of Cobalt containing Adenylate kinase from Gram-negative bacteria ''Desulfovibrio gigas'' [[3l0s]].
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==Biological Role==
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<b>References</b><br>
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[[Image: PPAR_Mechanism.png|400px|left|thumb| PPAR Mechanism of Action in the Human Body]]
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<references/>
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Transcription of individual genes in eukaryotic cells is controlled very precisely at a number of different levels. One key level is the binding of specific [[DNA]] binding transcriptional factors such as nuclear receptors, to facilitate RNA polymerase function. Unliganded PPARs form a heterodimer with retinoid X receptor (RXR), specifically RXRα. This heterodimer binds to the Peroxisome Proliferator Response Element (PPRE), a specific DNA sequence present in the promoter region of PPAR-regulated genes. <ref>PMID:11330046</ref> Also associated with this unliganded heterodimer is a co-repressor complex which possesses histone deacetylation activity, enforcing a tight chromatin structure which prevents gene transcription. <ref>PMID:15681609</ref> This co-repressor complex is released upon ligand binding (typical ligands include lipids and eicosanoids), allowing various co-activators and co-activator-associated proteins to be recruited. These protein complexes modulate chromatin remodeling as well as facilitate DNA unwinding and linkage to RNA polymerase II machinery, to begin transcription. Some PPAR related co-activators include CBP (Histone Acetylation), SRC-1,2,3 (Chromatin Acetylation), <ref>pmid:7539101</ref> PGC-1 (Recruit [http://en.wikipedia.org/wiki/Histone_acetyltransferase HAT activities]), PRIC-285,320 (Chromatin Remodeling via Helicase activity)<ref>PMID:11158331</ref>and PIMT (RNA Capping via methyltransferase activity)<ref>PMID:10381882</ref>.
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</StructureSection>
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Current revision

Crystal structure of cobalt bound adenylate kinase from Desulfovibrio gigas

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