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| - | [[Image:1mn7.jpg|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1mn7| PDB=1mn7 | SCENE= }} | | {{STRUCTURE_1mn7| PDB=1mn7 | SCENE= }} |
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| - | '''NDP kinase mutant (H122G;N119S;F64W) in complex with aBAZTTP'''
| + | ===NDP kinase mutant (H122G;N119S;F64W) in complex with aBAZTTP=== |
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| - | ==Overview==
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| - | Antiviral nucleoside analog therapies rely on their incorporation by viral DNA polymerases/reverse transcriptase leading to chain termination. The analogs (3'-deoxy-3'-azidothymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and other dideoxynucleosides) are sequentially converted into triphosphate by cellular kinases of the nucleoside salvage pathway and are often poor substrates of these enzymes. Nucleoside diphosphate (NDP) kinase phosphorylates the diphosphate derivatives of the analogs with an efficiency some 10(4) lower than for its natural substrates. Kinetic and structural studies of Dictyostelium and human NDP kinases show that the sugar 3'-OH, absent from all antiviral analogs, is required for catalysis. To improve the catalytic efficiency of NDP kinase on the analogs, we engineered several mutants with a protein OH group replacing the sugar 3'-OH. The substitution of Asn-115 in Ser and Leu-55 in His results in an NDP kinase mutant with an enhanced ability to phosphorylate antiviral derivatives. Transfection of the mutant enzyme in Escherichia coli results in an increased sensitivity to AZT. An x-ray structure at 2.15-A resolution of the Dictyostelium enzyme bearing the serine substitution in complex with the R(p)-alpha-borano-triphosphate derivative of AZT shows that the enhanced activity reflects an improved geometry of binding and a favorable interaction of the 3'-azido group with the engineered serine.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_12171931}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 12171931 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_12171931}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Veron, m.]] | | [[Category: Veron, m.]] |
| | [[Category: Ndp kinase-abazttp complex]] | | [[Category: Ndp kinase-abazttp complex]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 01:26:40 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jul 3 00:26:13 2008'' |
Revision as of 21:26, 2 July 2008
Template:STRUCTURE 1mn7
NDP kinase mutant (H122G;N119S;F64W) in complex with aBAZTTP
Template:ABSTRACT PUBMED 12171931
About this Structure
1MN7 is a Single protein structure of sequence from Dictyostelium discoideum. Full crystallographic information is available from OCA.
Reference
Improving nucleoside diphosphate kinase for antiviral nucleotide analogs activation., Gallois-Montbrun S, Schneider B, Chen Y, Giacomoni-Fernandes V, Mulard L, Morera S, Janin J, Deville-Bonne D, Veron M, J Biol Chem. 2002 Oct 18;277(42):39953-9. Epub 2002 Aug 8. PMID:12171931
Page seeded by OCA on Thu Jul 3 00:26:13 2008
