title: Crystal structure of human cyclin-dependent kinase-2 complex with MK2 inhibitor TEI-I01800: insight into the selectivity.
abstract: Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2) is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the MK2-TEI-I01800 complex has been reported; its Gly-rich loop was found to form an α-helix, not a β-sheet as has been observed for other Ser/Thr kinases. TEI-I01800 is 177-fold selective against MK2 compared with CDK2; in order to understand the inhibitory mechanism of TEI-I01800, the cyclin-dependent kinase 2 (CDK2) complex structure with TEI-I01800 was determined at 2.0 Å resolution. Interestingly, the Gly-rich loop of CDK2 formed a β-sheet that was different from that of MK2. In MK2, TEI-I01800 changed the secondary structure of the Gly-rich loop from a β-sheet to an α-helix by collision between Leu70 and a p-ethoxyphenyl group at the 7-position and bound to MK2. However, for CDK2, TEI-I01800 bound to CDK2 without this structural change and lost the interaction with the substituent at the 7-position. In summary, the results of this study suggest that the reason for the selectivity of TEI-I01800 is the favourable conformation of TEI-I01800 itself, making it suitable for binding to the α-form MK2.
authors.affiliation: Teijin Institute for Bio-medical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Fujino
authors.forename: Kei
authors.initials: K
authors.lastname: Fukushima
authors.forename: Takaharu
authors.initials: T
authors.lastname: Kubota
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kosugi
authors.forename: Midori
authors.initials: M
authors.lastname: Takimoto-Kamimura
mesh_terms: D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry*; D006801:Humans; D011487:Protein Conformation
chemical_list: C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; MAPKAP-K2; MK2; X-ray; inhibitor; structure