2a9z: Difference between revisions

Revision as of 17:25, 21 February 2008

Crystal structure of T. gondii adenosine kinase complexed with N6-dimethyladenosine and AMP-PCP

OverviewOverview

Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure-activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, the AK-6-methyl mercaptopurine riboside (MMPR) complex and the AK-MMPR-AMP-PCP complex were determined to 1.35, 1.35, 1.75 and 1.75 A resolution, respectively. These structures reveal a conformation intermediate between open and closed, with a small lid-domain rotation of 12 degrees . Residues Gly143-X-X-Gly146 undergo torsional changes upon substrate binding, which together with a Gly68-Gly69 switch induces a hinge bending of the lid domain. The intermediate conformation suggests that ATP binding is independent of adenosine binding. Orienting the gamma-phosphate group of ATP into the optimal catalytic position may be the last step before the onset of chemical catalysis and may require the translocation of Arg136 following the complete closure of the lid domain. 6-Substituted purine-nucleoside analogs are accommodated in a hydrophobic cavity. Modification at the N6 or C6 position of the nucleoside would affect the interactions with the surrounding residues and the binding affinity.

About this StructureAbout this Structure

2A9Z is a Single protein structure of sequence from Toxoplasma gondii with , , and as ligands. Active as Adenosine kinase, with EC number 2.7.1.20 Full crystallographic information is available from OCA.

ReferenceReference

Substrate analogs induce an intermediate conformational change in Toxoplasma gondii adenosine kinase., Zhang Y, El Kouni MH, Ealick SE, Acta Crystallogr D Biol Crystallogr. 2007 Feb;63(Pt 2):126-34. Epub 2007, Jan 16. PMID:17242506

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-[[Image:2a9z.gif|left|200px]]<br /><applet load="2a9z" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="2a9z, resolution 1.35&Aring;" />
 '''Crystal structure of T. gondii adenosine kinase complexed with N6-dimethyladenosine and AMP-PCP'''<br />
 ==Overview==
-Adenosine kinase (AK) is a key enzyme in purine metabolism in the, ubiquitous intracellular parasite Toxoplasma gondii and is a potential, chemotherapeutic target for the treatment of T. gondii infections. To, better understand the structure-activity relationship of 6-substituted, purine ribosides, the structures of the T. gondii, AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, the, AK-6-methyl mercaptopurine riboside (MMPR) complex and the AK-MMPR-AMP-PCP, complex were determined to 1.35, 1.35, 1.75 and 1.75 A resolution, respectively. These structures reveal a conformation intermediate between, open and closed, with a small lid-domain rotation of 12 degrees . Residues, Gly143-X-X-Gly146 undergo torsional changes upon substrate binding, which, together with a Gly68-Gly69 switch induces a hinge bending of the lid, domain. The intermediate conformation suggests that ATP binding is, independent of adenosine binding. Orienting the gamma-phosphate group of, ATP into the optimal catalytic position may be the last step before the, onset of chemical catalysis and may require the translocation of Arg136, following the complete closure of the lid domain. 6-Substituted, purine-nucleoside analogs are accommodated in a hydrophobic cavity., Modification at the N6 or C6 position of the nucleoside would affect the, interactions with the surrounding residues and the binding affinity.
+Adenosine kinase (AK) is a key enzyme in purine metabolism in the ubiquitous intracellular parasite Toxoplasma gondii and is a potential chemotherapeutic target for the treatment of T. gondii infections. To better understand the structure-activity relationship of 6-substituted purine ribosides, the structures of the T. gondii AK-N6,N6-dimethyladenosine (DMA) complex, the AK-DMA-AMP-PCP complex, the AK-6-methyl mercaptopurine riboside (MMPR) complex and the AK-MMPR-AMP-PCP complex were determined to 1.35, 1.35, 1.75 and 1.75 A resolution, respectively. These structures reveal a conformation intermediate between open and closed, with a small lid-domain rotation of 12 degrees . Residues Gly143-X-X-Gly146 undergo torsional changes upon substrate binding, which together with a Gly68-Gly69 switch induces a hinge bending of the lid domain. The intermediate conformation suggests that ATP binding is independent of adenosine binding. Orienting the gamma-phosphate group of ATP into the optimal catalytic position may be the last step before the onset of chemical catalysis and may require the translocation of Arg136 following the complete closure of the lid domain. 6-Substituted purine-nucleoside analogs are accommodated in a hydrophobic cavity. Modification at the N6 or C6 position of the nucleoside would affect the interactions with the surrounding residues and the binding affinity.
 ==About this Structure==
-A9Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii] with CL, NA, 26A and ACP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosine_kinase Adenosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.20 2.7.1.20] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2A9Z OCA].
+A9Z is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii] with <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=NA:'>NA</scene>, <scene name='pdbligand=26A:'>26A</scene> and <scene name='pdbligand=ACP:'>ACP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Adenosine_kinase Adenosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.20 2.7.1.20] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2A9Z OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Toxoplasma gondii]]
-[[Category: Ealick, S.E.]]
+[[Category: Ealick, S E.]]
-[[Category: Kouni, M.H.el.]]
+[[Category: Kouni, M H.el.]]
 [[Category: Zhang, Y.]]
 [[Category: 26A]]
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 [[Category: ribokinase fold; alpha/beta; intermediate conformation]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 08:00:27 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:25:19 2008''