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Mycobacterium tuberculosis Shikimate Kinase Inhibitors: Design and Simulation Studies of the Catalytic Turnover

Overview of attention for article published in Journal of the American Chemical Society, August 2013
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Title
Mycobacterium tuberculosis Shikimate Kinase Inhibitors: Design and Simulation Studies of the Catalytic Turnover
Published in
Journal of the American Chemical Society, August 2013
DOI 10.1021/ja405853p
Pubmed ID
Authors

Beatriz Blanco, Verónica Prado, Emilio Lence, José M. Otero, Carmela Garcia-Doval, Mark J. van Raaij, Antonio L. Llamas-Saiz, Heather Lamb, Alastair R. Hawkins, Concepción González-Bello

Abstract

Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 Å. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 92 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Germany 1 1%
Argentina 1 1%
Canada 1 1%
Unknown 89 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 16 17%
Researcher 14 15%
Student > Master 12 13%
Student > Bachelor 9 10%
Professor > Associate Professor 6 7%
Other 14 15%
Unknown 21 23%
Readers by discipline Count As %
Chemistry 24 26%
Biochemistry, Genetics and Molecular Biology 12 13%
Agricultural and Biological Sciences 10 11%
Medicine and Dentistry 5 5%
Immunology and Microbiology 3 3%
Other 8 9%
Unknown 30 33%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 September 2013.
All research outputs
#17,695,202
of 22,719,618 outputs
Outputs from Journal of the American Chemical Society
#57,781
of 61,837 outputs
Outputs of similar age
#141,792
of 197,321 outputs
Outputs of similar age from Journal of the American Chemical Society
#468
of 548 outputs
Altmetric has tracked 22,719,618 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 61,837 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.8. This one is in the 5th percentile – i.e., 5% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 197,321 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 25th percentile – i.e., 25% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 548 others from the same source and published within six weeks on either side of this one. This one is in the 13th percentile – i.e., 13% of its contemporaries scored the same or lower than it.