title: Structure of human protein kinase CK2 alpha 2 with a potent indazole-derivative inhibitor.
abstract: Casein kinase 2 (CK2) is a serine/threonine kinase that functions as a heterotetramer composed of two catalytic subunits (CK2alpha1 or CK2alpha2) and two regulatory subunits (CK2beta). The two isozymes CK2alpha1 and CK2alpha2 play distinguishable roles in healthy subjects and in patients with diseases such as cancer, respectively. In order to develop novel CK2alpha1-selective inhibitors, the crystal structure of human CK2alpha2 (hCK2alpha2) complexed with a potent CK2alpha inhibitor which binds to the active site of hCK2alpha2 was determined and compared with that of human CK2alpha1. While the two isozymes exhibited a high similarity with regard to the active site, the largest structural difference between the isoforms occurred in the beta4-beta5 loop responsible for the CK2alpha-CK2beta interface. The top of the N-terminal segment interacted with the beta4-beta5 loop via a hydrogen bond in hCK2alpha2 but not in hCK2alpha1. Thus, the CK2alpha-CK2beta interface is a likely target candidate for the production of selective CK2alpha1 inhibitors.
authors.affiliation: Graduate School of Sciences, Osaka Prefecture University, Osaka 599-8530, Japan.
authors.forename: Tetsuko
authors.initials: T
authors.lastname: Nakaniwa
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Toshiji
authors.initials: T
authors.lastname: Tada
authors.forename: Isao
authors.initials: I
authors.lastname: Nakanishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitaura
authors.forename: Yamato
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.forename: Gozoh
authors.initials: G
authors.lastname: Tsujimoto
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary / Q000502:physiology
chemical_list: D007191:Indazoles; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D047390:Casein Kinase II