6T28

Crystal structure of human calmodulin-dependent protein kinase 1D (CAMK1D) bound to compound 19 (CS640)

これはPDB形式変換不可エントリーです。

6T28 の概要

• エントリーDOI: 10.2210/pdb6t28/pdb
• 分子名称: Calcium/calmodulin-dependent protein kinase type 1D, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: inhibitor, complex, kinase, structural genomics, structural genomics consortium, sgc, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43844.71

構造登録者

Kraemer, A.,Sorrell, F.,Butterworth, S.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2019-10-08, 公開日: 2019-11-13, 最終更新日: 2024-01-24)

主引用文献

Fromont, C.,Atzori, A.,Kaur, D.,Hashmi, L.,Greco, G.,Cabanillas, A.,Nguyen, H.V.,Jones, D.H.,Garzon, M.,Varela, A.,Stevenson, B.,Iacobini, G.P.,Lenoir, M.,Rajesh, S.,Box, C.,Kumar, J.,Grant, P.,Novitskaya, V.,Morgan, J.,Sorrell, F.J.,Redondo, C.,Kramer, A.,Harris, C.J.,Leighton, B.,Vickers, S.P.,Cheetham, S.C.,Kenyon, C.,Grabowska, A.M.,Overduin, M.,Berditchevski, F.,Weston, C.J.,Knapp, S.,Fischer, P.M.,Butterworth, S.
Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesityin VivoMouse Model.
J.Med.Chem., 63:6784-6801, 2020

PubMed Abstract: Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first validation of CaMK1D as a target for diabetes therapeutics.

PubMed: 32433887
DOI: 10.1021/acs.jmedchem.9b01803

実験手法

X-RAY DIFFRACTION (1.55 Å)