title: Structural and evolutionary divergence of cyclic nucleotide binding domains in eukaryotic pathogens: Implications for drug design.
abstract: Many cellular functions in eukaryotic pathogens are mediated by the cyclic nucleotide binding (CNB) domain, which senses second messengers such as cyclic AMP and cyclic GMP. Although CNB domain-containing proteins have been identified in many pathogenic organisms, an incomplete understanding of how CNB domains in pathogens differ from other eukaryotic hosts has hindered the development of selective inhibitors for CNB domains associated with infectious diseases. Here, we identify and classify CNB domain-containing proteins in eukaryotic genomes to understand the evolutionary basis for CNB domain functional divergence in pathogens. We identify 359 CNB domain-containing proteins in 31 pathogenic organisms and classify them into distinct subfamilies based on sequence similarity within the CNB domain as well as functional domains associated with the CNB domain. Our study reveals novel subfamilies with pathogen-specific variations in the phosphate-binding cassette. Analyzing these variations in light of existing structural and functional data provides new insights into ligand specificity and promiscuity and clues for drug design. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Eileen J
authors.initials: EJ
authors.lastname: Kennedy
authors.affiliation: Department of Biochemistry, University of Kassel, Germany.
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Herberg
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.affiliation: Department of Chemistry & Biochemistry and Pharmacology, University of CA, San Diego, USA.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.affiliation: INSERM U1016, CNRS UMR8104, Cochin Institute, Paris, 75014 France; Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes - Sorbonne Paris Cité, France.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA; Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA. Electronic address: kannan@bmb.uga.edu.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
mesh_terms: D000242:Cyclic AMP / Q000737:chemistry / Q000235:genetics; D006152:Cyclic GMP / Q000737:chemistry / Q000235:genetics; D015195:Drug Design; D019143:Evolution, Molecular; D016678:Genome; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D007239:Infections / Q000235:genetics / Q000473:pathology; D010802:Phylogeny; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D011494:Protein Kinases; D006152:Cyclic GMP
keywords: Allosteric regulation; Bioinformatics; Cyclic nucleotide signaling; Evolution; Pathogenic variation; Phylogeny
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