title: The ATP-binding site of protein kinase CK2 holds a positive electrostatic area and conserved water molecules.
abstract: CK2 is a highly pleiotropic Ser/Thr protein kinase that is able to promote cell survival and enhance the tumour phenotype under specific circumstances. We have determined the crystal structure of three new complexes with tetrabromobenzimidazole derivatives that display K(i) values between 0.15 and 0.30 microM. A comparative analysis of these data with those of four other inhibitors of the same family revealed the presence of some highly conserved water molecules in the ATP-binding site. These waters reside near Lys68, in an area with a positive electrostatic potential that is able to attract and orient negatively charged ligands. The presence of this positive region and two unique bulky residues that are typical of CK2, Ile66 and Ile174, play a critical role in determining the ligand orientation and binding selectivity.
authors.affiliation: Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy. roberto. battistutta@unipd.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Battistutta
authors.forename: Marco
authors.initials: M
authors.lastname: Mazzorana
authors.forename: Laura
authors.initials: L
authors.lastname: Cendron
authors.forename: Andrea
authors.initials: A
authors.lastname: Bortolato
authors.forename: Stefania
authors.initials: S
authors.lastname: Sarno
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Kazimierczuk
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zanotti
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D047390:Casein Kinase II / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007532:Isoleucine / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D055672:Static Electricity; D014867:Water / Q000737:chemistry*
chemical_list: C475924:4,5,6,7-tetrabromobenzimidazole; D001562:Benzimidazoles; D008024:Ligands; D007532:Isoleucine; D014867:Water; D000255:Adenosine Triphosphate; D047390:Casein Kinase II; D008239:Lysine