Document Detail


Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights.
MedLine Citation:
PMID:  16027359     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Glutamine synthetase catalyzes the ligation of glutamate and ammonia to form glutamine, with the resulting hydrolysis of ATP. The enzyme is a central component of bacterial nitrogen metabolism and is a potential drug target. Here, we report a high-yield recombinant expression system for glutamine synthetase of Mycobacterium tuberculosis together with a simple purification. The procedure allowed the structure of a complex with a phosphorylated form of the inhibitor methionine sulfoximine, magnesium, and ADP to be solved by molecular replacement and refined at 2.1-A resolution. To our knowledge, this study provides the first reported structure for a taut form of the M. tuberculosis enzyme, similar to that observed for the Salmonella enzyme earlier. The phospho compound, generated in situ by an active enzyme, mimics the phosphorylated tetrahedral adduct at the transition state. Some differences in ligand interactions of the protein with both phosphorylated compound and nucleotide are observed compared with earlier structures; a third metal ion also is found. The importance of these differences in the catalytic mechanism is discussed; the results will help guide the search for specific inhibitors of potential therapeutic interest.
Authors:
Wojciech W Krajewski; T Alwyn Jones; Sherry L Mowbray
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-07-18
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  102     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-07-27     Completed Date:  2005-12-29     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10499-504     Citation Subset:  IM    
Affiliation:
Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden.
Data Bank Information
Bank Name/Acc. No.:
PDB/2BVC
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MeSH Terms
Descriptor/Qualifier:
Adenosine Diphosphate / metabolism
Cloning, Molecular
Crystallography, X-Ray
DNA Primers
Glutamate-Ammonia Ligase / chemistry*,  isolation & purification*
Magnesium / metabolism
Methionine Sulfoximine / metabolism
Models, Molecular*
Mycobacterium tuberculosis / enzymology*
Protein Conformation
Chemical
Reg. No./Substance:
0/DNA Primers; 1982-67-8/Methionine Sulfoximine; 58-64-0/Adenosine Diphosphate; 7439-95-4/Magnesium; EC 6.3.1.2/Glutamate-Ammonia Ligase
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