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4tmk

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{{STRUCTURE_4tmk| PDB=4tmk | SCENE= }}
{{STRUCTURE_4tmk| PDB=4tmk | SCENE= }}
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'''COMPLEX OF E. COLI THYMIDYLATE KINASE WITH THE BISUBSTRATE INHIBITOR TP5A'''
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===COMPLEX OF E. COLI THYMIDYLATE KINASE WITH THE BISUBSTRATE INHIBITOR TP5A===
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==Overview==
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The crystal structures of Escherichia coli thymidylate kinase (TmpK) in complex with P1-(5'-adenosyl)-P5-(5'-thymidyl)pentaphosphate and P1-(5'-adenosyl)P5-[5'-(3'-azido-3'-deoxythymidine)] pentaphosphate have been solved to 2.0-A and 2.2-A resolution, respectively. The overall structure of the bacterial TmpK is very similar to that of yeast TmpK. In contrast to the human and yeast TmpKs, which phosphorylate 3'-azido-3'-deoxythymidine 5'-monophosphate (AZT-MP) at a 200-fold reduced turnover number (kcat) in comparison to the physiological substrate dTMP, reduction of kcat is only 2-fold for the bacterial enzyme. The different kinetic properties toward AZT-MP between the eukaryotic TmpKs and E. coli TmpK can be rationalized by the different ways in which these enzymes stabilize the presumed transition state and the different manner in which a carboxylic acid side chain in the P loop interacts with the deoxyribose of the monophosphate. Yeast TmpK interacts with the 3'-hydroxyl of dTMP through Asp-14 of the P loop in a bidentate manner: binding of AZT-MP results in a shift of the P loop to accommodate the larger substituent. In E. coli TmpK, the corresponding residue is Glu-12, and it interacts in a side-on fashion with the 3'-hydroxyl of dTMP. This different mode of interaction between the P loop carboxylic acid with the 3' substituent of the monophosphate deoxyribose allows the accommodation of an azido group in the case of the E. coli enzyme without significant P loop movement. In addition, although the yeast enzyme uses Arg-15 (a glycine in E. coli) to stabilize the transition state, E. coli seems to use Arg-153 from a region termed Lid instead. Thus, the binding of AZT-MP to the yeast TmpK results in the shift of a catalytic residue, which is not the case for the bacterial kinase.
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{{ABSTRACT_PUBMED_9826650}}
==About this Structure==
==About this Structure==
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[[Category: Schlichting, I.]]
[[Category: Schlichting, I.]]
[[Category: Atp:dtmp phosphotransferase]]
[[Category: Atp:dtmp phosphotransferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jul 3 13:52:15 2008''

Revision as of 10:52, 3 July 2008

Image:4tmk.png

Template:STRUCTURE 4tmk

COMPLEX OF E. COLI THYMIDYLATE KINASE WITH THE BISUBSTRATE INHIBITOR TP5A

Template:ABSTRACT PUBMED 9826650

About this Structure

4TMK is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.

Reference

Structural basis for efficient phosphorylation of 3'-azidothymidine monophosphate by Escherichia coli thymidylate kinase., Lavie A, Ostermann N, Brundiers R, Goody RS, Reinstein J, Konrad M, Schlichting I, Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14045-50. PMID:9826650

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