2b8t

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(New page: 200px<br /><applet load="2b8t" size="450" color="white" frame="true" align="right" spinBox="true" caption="2b8t, resolution 2.00&Aring;" /> '''Crystal structure of...)
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'''Crystal structure of Thymidine Kinase from U.urealyticum in complex with thymidine'''<br />
'''Crystal structure of Thymidine Kinase from U.urealyticum in complex with thymidine'''<br />
==Overview==
==Overview==
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Thymidine kinases have been found in most organisms, from viruses and, bacteria to mammals. Ureaplasma urealyticum (parvum), which belongs to the, class of cell-wall-lacking Mollicutes, has no de novo synthesis of DNA, precursors and therefore has to rely on the salvage pathway. Thus, thymidine kinase (Uu-TK) is the key enzyme in dTTP synthesis. Recently the, 3D structure of Uu-TK was determined in a feedback inhibitor complex, demonstrating that a lasso-like loop binds the thymidine moiety of the, feedback inhibitor by hydrogen bonding to main-chain atoms. Here the, structure with the substrate deoxythymidine is presented. The substrate, binds similarly to the deoxythymidine part of the feedback inhibitor, and, the lasso-like loop binds the base and deoxyribose moieties as in the, complex determined previously. The catalytic base, Glu97, has a different, position in the substrate complex from that in the complex with the, feedback inhibitor, having moved in closer to the 5'-OH of the substrate, to form a hydrogen bond. The phosphorylation of and inhibition by several, nucleoside analogues were investigated and are discussed in the light of, the substrate binding pocket, in comparison with human TK1. Kinetic, differences between Uu-TK and human TK1 were observed that may be, explained by structural differences. The tight interaction with the, substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2'-Ara position, but larger, substitutions at the 3' position of the deoxyribose.
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Thymidine kinases have been found in most organisms, from viruses and bacteria to mammals. Ureaplasma urealyticum (parvum), which belongs to the class of cell-wall-lacking Mollicutes, has no de novo synthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus, thymidine kinase (Uu-TK) is the key enzyme in dTTP synthesis. Recently the 3D structure of Uu-TK was determined in a feedback inhibitor complex, demonstrating that a lasso-like loop binds the thymidine moiety of the feedback inhibitor by hydrogen bonding to main-chain atoms. Here the structure with the substrate deoxythymidine is presented. The substrate binds similarly to the deoxythymidine part of the feedback inhibitor, and the lasso-like loop binds the base and deoxyribose moieties as in the complex determined previously. The catalytic base, Glu97, has a different position in the substrate complex from that in the complex with the feedback inhibitor, having moved in closer to the 5'-OH of the substrate to form a hydrogen bond. The phosphorylation of and inhibition by several nucleoside analogues were investigated and are discussed in the light of the substrate binding pocket, in comparison with human TK1. Kinetic differences between Uu-TK and human TK1 were observed that may be explained by structural differences. The tight interaction with the substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2'-Ara position, but larger substitutions at the 3' position of the deoxyribose.
==About this Structure==
==About this Structure==
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2B8T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ureaplasma_parvum Ureaplasma parvum] with ZN, THM and TRS as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidine_kinase Thymidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.21 2.7.1.21] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2B8T OCA].
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2B8T is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Ureaplasma_parvum Ureaplasma parvum] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=THM:'>THM</scene> and <scene name='pdbligand=TRS:'>TRS</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Thymidine_kinase Thymidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.21 2.7.1.21] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2B8T OCA].
==Reference==
==Reference==
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[[Category: zinc-binding domain]]
[[Category: zinc-binding domain]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 08:38:44 2007''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:35:17 2008''

Revision as of 14:35, 21 February 2008

Image:2b8t.gif

2b8t, resolution 2.00Å

Drag the structure with the mouse to rotate

Crystal structure of Thymidine Kinase from U.urealyticum in complex with thymidine

Overview

Thymidine kinases have been found in most organisms, from viruses and bacteria to mammals. Ureaplasma urealyticum (parvum), which belongs to the class of cell-wall-lacking Mollicutes, has no de novo synthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus, thymidine kinase (Uu-TK) is the key enzyme in dTTP synthesis. Recently the 3D structure of Uu-TK was determined in a feedback inhibitor complex, demonstrating that a lasso-like loop binds the thymidine moiety of the feedback inhibitor by hydrogen bonding to main-chain atoms. Here the structure with the substrate deoxythymidine is presented. The substrate binds similarly to the deoxythymidine part of the feedback inhibitor, and the lasso-like loop binds the base and deoxyribose moieties as in the complex determined previously. The catalytic base, Glu97, has a different position in the substrate complex from that in the complex with the feedback inhibitor, having moved in closer to the 5'-OH of the substrate to form a hydrogen bond. The phosphorylation of and inhibition by several nucleoside analogues were investigated and are discussed in the light of the substrate binding pocket, in comparison with human TK1. Kinetic differences between Uu-TK and human TK1 were observed that may be explained by structural differences. The tight interaction with the substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2'-Ara position, but larger substitutions at the 3' position of the deoxyribose.

About this Structure

2B8T is a Single protein structure of sequence from Ureaplasma parvum with , and as ligands. Active as Thymidine kinase, with EC number 2.7.1.21 Full crystallographic information is available from OCA.

Reference

Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme., Kosinska U, Carnrot C, Eriksson S, Wang L, Eklund H, FEBS J. 2005 Dec;272(24):6365-72. PMID:16336273

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