1e2q

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(New page: 200px<br /> <applet load="1e2q" size="450" color="white" frame="true" align="right" spinBox="true" caption="1e2q, resolution 1.7&Aring;" /> '''HUMAN THYMIDYLATE KI...)
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'''HUMAN THYMIDYLATE KINASE COMPLEXED WITH TP5A AND A MAGNESIUM-ION'''<br />
'''HUMAN THYMIDYLATE KINASE COMPLEXED WITH TP5A AND A MAGNESIUM-ION'''<br />
==Overview==
==Overview==
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BACKGROUND: Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase, that catalyzes the reversible phosphoryltransfer between ATP and TMP to, yield ADP and TDP. In addition to its vital role in supplying precursors, for DNA synthesis, human TMPK has an important medical role participating, in the activation of a number of anti-HIV prodrugs. RESULTS: Crystal, structures of human TMPK in complex with TMP and ADP, TMP and the ATP, analog AppNHp, TMP with ADP and the phosphoryl analog AlF(3), TDP and ADP, and the bisubstrate analog TP(5)A were determined. The conformations of, the P-loop, the LID region, and the adenine-binding loop vary according to, the nature of the complex. Substitution of ADP by AppNHp results in, partial closure of the P-loop and the rotation of the TMP phosphate group, to a catalytically unfavorable position, which rotates back in the AlF(3), complex to a position suitable for in-line attack. In the fully closed, state observed in the TP(5)A and the TDP-ADP complexes, Asp15 interacts, strongly with the 3'-hydroxyl group of TMP. CONCLUSIONS: The observed, changes of nucleotide state and conformation and the corresponding protein, structural changes are correlated with intermediates occurring along the, reaction coordinate and show the sequence of events occurring during, phosphate transfer. The low catalytic activity of human TMPK appears to be, determined by structural changes required to achieve catalytic competence, and it is suggested that a mechanism might exist to accelerate the, activity.
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BACKGROUND: Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes the reversible phosphoryltransfer between ATP and TMP to yield ADP and TDP. In addition to its vital role in supplying precursors for DNA synthesis, human TMPK has an important medical role participating in the activation of a number of anti-HIV prodrugs. RESULTS: Crystal structures of human TMPK in complex with TMP and ADP, TMP and the ATP analog AppNHp, TMP with ADP and the phosphoryl analog AlF(3), TDP and ADP, and the bisubstrate analog TP(5)A were determined. The conformations of the P-loop, the LID region, and the adenine-binding loop vary according to the nature of the complex. Substitution of ADP by AppNHp results in partial closure of the P-loop and the rotation of the TMP phosphate group to a catalytically unfavorable position, which rotates back in the AlF(3) complex to a position suitable for in-line attack. In the fully closed state observed in the TP(5)A and the TDP-ADP complexes, Asp15 interacts strongly with the 3'-hydroxyl group of TMP. CONCLUSIONS: The observed changes of nucleotide state and conformation and the corresponding protein structural changes are correlated with intermediates occurring along the reaction coordinate and show the sequence of events occurring during phosphate transfer. The low catalytic activity of human TMPK appears to be determined by structural changes required to achieve catalytic competence and it is suggested that a mechanism might exist to accelerate the activity.
==About this Structure==
==About this Structure==
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1E2Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, TMP and ATP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1E2Q OCA].
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1E2Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=TMP:'>TMP</scene> and <scene name='pdbligand=ATP:'>ATP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/dTMP_kinase dTMP kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.9 2.7.4.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E2Q OCA].
==Reference==
==Reference==
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[[Category: dTMP kinase]]
[[Category: dTMP kinase]]
[[Category: Brundiers, R.]]
[[Category: Brundiers, R.]]
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[[Category: Goody, R.S.]]
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[[Category: Goody, R S.]]
[[Category: Konrad, M.]]
[[Category: Konrad, M.]]
[[Category: Lavie, A.]]
[[Category: Lavie, A.]]
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[[Category: thymidylate kinase]]
[[Category: thymidylate kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:23:07 2008''

Revision as of 10:23, 21 February 2008

Image:1e2q.gif

1e2q, resolution 1.7Å

Drag the structure with the mouse to rotate

HUMAN THYMIDYLATE KINASE COMPLEXED WITH TP5A AND A MAGNESIUM-ION

Overview

BACKGROUND: Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes the reversible phosphoryltransfer between ATP and TMP to yield ADP and TDP. In addition to its vital role in supplying precursors for DNA synthesis, human TMPK has an important medical role participating in the activation of a number of anti-HIV prodrugs. RESULTS: Crystal structures of human TMPK in complex with TMP and ADP, TMP and the ATP analog AppNHp, TMP with ADP and the phosphoryl analog AlF(3), TDP and ADP, and the bisubstrate analog TP(5)A were determined. The conformations of the P-loop, the LID region, and the adenine-binding loop vary according to the nature of the complex. Substitution of ADP by AppNHp results in partial closure of the P-loop and the rotation of the TMP phosphate group to a catalytically unfavorable position, which rotates back in the AlF(3) complex to a position suitable for in-line attack. In the fully closed state observed in the TP(5)A and the TDP-ADP complexes, Asp15 interacts strongly with the 3'-hydroxyl group of TMP. CONCLUSIONS: The observed changes of nucleotide state and conformation and the corresponding protein structural changes are correlated with intermediates occurring along the reaction coordinate and show the sequence of events occurring during phosphate transfer. The low catalytic activity of human TMPK appears to be determined by structural changes required to achieve catalytic competence and it is suggested that a mechanism might exist to accelerate the activity.

About this Structure

1E2Q is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as dTMP kinase, with EC number 2.7.4.9 Full crystallographic information is available from OCA.

Reference

Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate., Ostermann N, Schlichting I, Brundiers R, Konrad M, Reinstein J, Veit T, Goody RS, Lavie A, Structure. 2000 Jun 15;8(6):629-42. PMID:10873853

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