Structural basis for feedback inhibition of the deoxyribonucleoside salvage pathway : studies of the Drosophila deoxyribonucleoside kinase
(2003) In Biochemistry 42(19). p.5706-5712- Abstract
Deoxyribonucleoside kinases are feedback inhibited by the final products of the salvage pathway, the deoxyribonucleoside triphosphates. In the present study, the mechanism of feedback inhibition is presented based on the crystal structure of a complex between the fruit fly deoxyribonucleoside kinase and its feedback inhibitor deoxythymidine triphosphate. The inhibitor was found to be bound as a bisubstrate inhibitor with its nucleoside part in the nucleoside binding site and with its phosphate groups partially occupying the phosphate donor site. The overall structure of the enzyme--inhibitor complex is very similar to the enzyme--substrate complexes with deoxythymidine and deoxycytidine, except for a conformational change within a... (More)
Deoxyribonucleoside kinases are feedback inhibited by the final products of the salvage pathway, the deoxyribonucleoside triphosphates. In the present study, the mechanism of feedback inhibition is presented based on the crystal structure of a complex between the fruit fly deoxyribonucleoside kinase and its feedback inhibitor deoxythymidine triphosphate. The inhibitor was found to be bound as a bisubstrate inhibitor with its nucleoside part in the nucleoside binding site and with its phosphate groups partially occupying the phosphate donor site. The overall structure of the enzyme--inhibitor complex is very similar to the enzyme--substrate complexes with deoxythymidine and deoxycytidine, except for a conformational change within a region otherwise directly involved in catalysis. This conformational change involves a magnesium ion, which is coordinated in the inhibitor complex to the phosphates and to the primary base, Glu52, that normally is positioned close to the 5'-OH of the substrate deoxyribose.
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- author
- Mikkelsen, Nils Egil ; Johansson, Kenth ; Karlsson, Andreas ; Knecht, Wolfgang LU ; Andersen, Gorm LU ; Piskur, Jure LU ; Munch-Petersen, Birgitte LU and Eklund, Hans
- publishing date
- 2003-05-20
- type
- Contribution to journal
- publication status
- published
- keywords
- Adenosine Triphosphate/metabolism, Animals, Binding Sites, Crystallography, X-Ray, Deoxyribonucleosides/metabolism, Drosophila melanogaster/enzymology, Feedback, Kinetics, Models, Molecular, Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors, Protein Conformation, Recombinant Proteins/chemistry, Static Electricity, Thymine Nucleotides/metabolism
- in
- Biochemistry
- volume
- 42
- issue
- 19
- pages
- 5706 - 5712
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- scopus:0038629174
- pmid:12741827
- ISSN
- 0006-2960
- DOI
- 10.1021/bi0340043
- language
- English
- LU publication?
- no
- id
- 355db5ee-79fa-46bb-b2f7-4b0f074453ec
- date added to LUP
- 2020-07-22 14:20:44
- date last changed
- 2024-01-02 15:00:47
@article{355db5ee-79fa-46bb-b2f7-4b0f074453ec,
abstract = {{<p>Deoxyribonucleoside kinases are feedback inhibited by the final products of the salvage pathway, the deoxyribonucleoside triphosphates. In the present study, the mechanism of feedback inhibition is presented based on the crystal structure of a complex between the fruit fly deoxyribonucleoside kinase and its feedback inhibitor deoxythymidine triphosphate. The inhibitor was found to be bound as a bisubstrate inhibitor with its nucleoside part in the nucleoside binding site and with its phosphate groups partially occupying the phosphate donor site. The overall structure of the enzyme--inhibitor complex is very similar to the enzyme--substrate complexes with deoxythymidine and deoxycytidine, except for a conformational change within a region otherwise directly involved in catalysis. This conformational change involves a magnesium ion, which is coordinated in the inhibitor complex to the phosphates and to the primary base, Glu52, that normally is positioned close to the 5'-OH of the substrate deoxyribose.</p>}},
author = {{Mikkelsen, Nils Egil and Johansson, Kenth and Karlsson, Andreas and Knecht, Wolfgang and Andersen, Gorm and Piskur, Jure and Munch-Petersen, Birgitte and Eklund, Hans}},
issn = {{0006-2960}},
keywords = {{Adenosine Triphosphate/metabolism; Animals; Binding Sites; Crystallography, X-Ray; Deoxyribonucleosides/metabolism; Drosophila melanogaster/enzymology; Feedback; Kinetics; Models, Molecular; Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors; Protein Conformation; Recombinant Proteins/chemistry; Static Electricity; Thymine Nucleotides/metabolism}},
language = {{eng}},
month = {{05}},
number = {{19}},
pages = {{5706--5712}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Biochemistry}},
title = {{Structural basis for feedback inhibition of the deoxyribonucleoside salvage pathway : studies of the Drosophila deoxyribonucleoside kinase}},
url = {{http://dx.doi.org/10.1021/bi0340043}},
doi = {{10.1021/bi0340043}},
volume = {{42}},
year = {{2003}},
}