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Solution structure and function of an essential CMP kinase of Streptococcus pneumoniae
Journal article   Open access   Peer reviewed

Solution structure and function of an essential CMP kinase of Streptococcus pneumoniae

Liping Yu, Jamey Mack, Philip J Hajduk, Steve J Kakavas, Anne Y C Saiki, Claude G Lerner and Edward T Olejniczak
Protein science, Vol.12(11), pp.2613-2621
11/2003
DOI: 10.1110/ps.03256803
PMCID: PMC2366957
PMID: 14573872
url
https://europepmc.org/articles/pmc2366957View
Published (Version of record) Open Access

Abstract

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 alpha-helices and two beta-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 beta-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.
 Amino Acid Sequence Bacterial Proteins - chemistry Bacterial Proteins - genetics Bacterial Proteins - metabolism Escherichia coli - enzymology Models, Molecular Molecular Sequence Data Nuclear Magnetic Resonance, Biomolecular Nucleoside-Phosphate Kinase - chemistry Nucleoside-Phosphate Kinase - genetics Nucleoside-Phosphate Kinase - metabolism Protein Conformation Protein Structure, Tertiary Sequence Alignment Solutions Streptococcus pneumoniae - enzymology Streptococcus pneumoniae - genetics

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