Linked Life Data

15327945

Source:http://linkedlifedata.com/resource/pubmed/id/15327945

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2004-8-25
pubmed:abstractText
Natural evolution has resulted in protein molecules displaying a wide range of binding properties that include extremes of affinity and specificity. A detailed understanding of the principles underlying protein structure-function relationships, particularly with respect to binding properties, would greatly enhance molecular engineering and ligand design studies. Here, we have analyzed the interactions of an aminoacyl-tRNA synthetase for which strong evolutionary pressure has enforced high specificity for substrate binding and catalysis. Electrostatic interactions have been identified as one efficient mechanism for enhancing binding specificity; as such, the effects of charged and polar groups were the focus of this study. The binding of glutaminyl-tRNA synthetase from Escherichia coli to several ligands, including the natural substrates, was analyzed. The electrostatic complementarity of the enzyme to its ligands was assessed using measures derived from affinity optimization theory. The results were independent of the details of the calculational parameters, including the value used for the protein dielectric constant. Glutamine and ATP, two of the natural ligands, were found to be extremely complementary to their binding sites, particularly in regions seen to make electrostatic interactions in the structure. These data suggest that the optimization of electrostatic interactions has played an important role in guiding the evolution of this enzyme. The results also show that the enzyme is able to effectively select for high affinity and specificity for the same chemical moieties both in the context of smaller substrates, and in that of a larger reactive intermediate. The regions of greatest non-complementarity between the enzyme and ligands are the portions of the ligand that make few polar contacts with the binding site, as well as the sites of chemical reaction, where overly strong electrostatic binding interactions with the substrate could hinder catalysis. The results also suggest that the negative charge on the phosphorus center of glutaminyl-adenylate plays an important role in the tight binding of this intermediate, and thus that adenylate analogs that preserve the negative charge in this region may bind substantially tighter than analogs where this group is replaced with a neutral group, such as the sulfamoyl family, which can make similar hydrogen bonds but is uncharged.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-2836
pubmed:author
pubmed:issnType
Print
pubmed:day
10
pubmed:volume
342
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
435-52
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Escherichia coli glutaminyl-tRNA synthetase is electrostatically optimized for binding of its cognate substrates.
pubmed:affiliation
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't