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Solution structure and function of an essential CMP kinase of Streptococcus pneumoniae
Author(s) -
Yu Liping,
Mack Jamey,
Hajduk Philip J.,
Kakavas Steve J.,
Saiki Anne Y.C.,
Lerner Claude G.,
Olejniczak Edward T.
Publication year - 2003
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.03256803
Subject(s) - streptococcus pneumoniae , protein kinase domain , binding site , kinase , chemistry , biophysics , binding domain , protein structure , enzyme , biochemistry , biology , stereochemistry , antibiotics , mutant , gene
Streptococcus pneumoniae is a major human pathogen that causes high mortality and morbidity and has developed resistance to many antibiotics. We show that the gene product from SP1603, identified from S. pneumoniae TIGR4, is a CMP kinase that is essential for bacterial growth. It represents an attractive drug target for the development of a novel antibiotic to overcome the problems of drug resistance development for this organism. Here we describe the three‐dimensional solution structure of the S. pneumoniae CMP kinase as determined by NMR spectroscopy. The structure consists of eight α‐helices and two β‐sheets that fold into the classical core domain, the substrate‐binding domain, and the LID domain. The three domains of the protein pack together to form a central cavity for substrate‐binding and enzymatic catalysis. The S. pneumoniae CMP kinase resembles the fold of the Escherichia coli homolog. An insertion of one residue is observed at the β‐turn in the substrate‐binding domain of the S. pneumoniae CMP kinase when compared with the E. coli homolog. Chemical shift perturbations caused by the binding of CMP, CDP, and ATP revealed that CMP or CDP binds to the junction between the core and substrate‐binding domains, whereas ATP binds to the junction between the core and LID domains. From NMR relaxation studies, we determined that the loops in the LID domain are highly mobile. These mobile loops could aid in the closing/opening of the LID domain during enzyme catalysis.