title: Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state.
abstract: Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 Å resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short α-helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the αC-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the γ-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices.
authors.affiliation: PharmAxess, Inc., 3-9-12, Matsubara-cho, Akishima, Tokyo 196-8666, Japan. t-matumo@rigaku.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Hitomi
authors.initials: H
authors.lastname: Matsuzaka
authors.forename: Ryoko
authors.initials: R
authors.lastname: Nakai
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kirii
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokota
authors.forename: Toshiji
authors.initials: T
authors.lastname: Tada
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human