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  Structural characterization of the closed conformation of mouse guanylate kinase

Sekulic, N., Shuvalova, L., Spangenberg, O., Konrad, M., & Lavie, A. (2002). Structural characterization of the closed conformation of mouse guanylate kinase. Journal of Biological Chemistry, 277(33), 30236-30243. Retrieved from http://www.jbc.org/content/277/33/30236.full.pdf+html.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-F335-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-E232-8
Genre: Journal Article

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Sekulic, N., Author
Shuvalova, L., Author
Spangenberg, O.1, Author              
Konrad, M.2, Author              
Lavie, A., Author
Affiliations:
1Department of Molecular Genetics, MPI for biophysical chemistry, Max Planck Society, ou_578622              
2Research Group of Enzyme Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578612              

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 Abstract: Guanylate kinase (GMPK) is a nucleoside monophosphate kinase that catalyzes the reversible phosphoryl transfer from ATP to GMP to yield ADP and GDP. In addition to phosphorylating GMP, antiviral prodrugs such as acyclovir, ganciclovir, and carbovir and anticancer prodrugs such as the thiopurines are dependent on GMPK for their activation. Hence, structural information on mammalian GMPK could play a role in the design of improved antiviral and antineoplastic agents. Here we present the structure of the mouse enzyme in an abortive complex with the nucleotides ADP and GMP, refined at 2.1 Angstrom resolution with a final crystallographic R factor of 0.19 (R-free = 0.23). Guanylate kinase is a member of the nucleoside monophosphate (NMP) kinase family, a family of enzymes that despite having a low primary structure identity share a similar fold, which consists of three structurally distinct regions termed the CORE, LID, and NMP-binding regions. Previous studies on the yeast enzyme have shown that these parts move as rigid bodies upon substrate binding. It has been proposed that consecutive binding of substrates leads to "closing" of the active site bringing the NMP-binding and LID regions closer to each other and to the CORE region. Our structure, which is the first of any guanylate kinase with both substrates bound, supports this hypothesis. It also reveals the binding site of ATP and implicates arginines 44, 137, and 148 (in addition to the invariant P-loop lysine) as candidates for catalyzing the chemical step of the phosphoryl transfer.

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Language(s): eng - English
 Dates: 2002-08-16
 Publication Status: Published in print
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Title: Journal of Biological Chemistry
Source Genre: Journal
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Pages: - Volume / Issue: 277 (33) Sequence Number: - Start / End Page: 30236 - 30243 Identifier: -