6VNM

JAK2 JH1 in complex with SY5-103

6VNM の概要

• エントリーDOI: 10.2210/pdb6vnm/pdb
• 分子名称: Tyrosine-protein kinase JAK2, 4-[1-(but-3-en-1-yl)-1H-pyrazol-4-yl]-N-[4-(piperidin-4-yl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-2-amine (3 entities in total)
• 機能のキーワード: janus associated kinase, jak2, kinase domain, jh1, kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 73737.92

構造登録者

Davis, R.R.,Schonbrunn, E. (登録日: 2020-01-29, 公開日: 2021-02-17, 最終更新日: 2023-11-15)

主引用文献

Davis, R.R.,Li, B.,Yun, S.Y.,Chan, A.,Nareddy, P.,Gunawan, S.,Ayaz, M.,Lawrence, H.R.,Reuther, G.W.,Lawrence, N.J.,Schonbrunn, E.
Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.
J.Med.Chem., 64:2228-2241, 2021

PubMed Abstract: The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.

PubMed: 33570945
DOI: 10.1021/acs.jmedchem.0c01952

実験手法

X-RAY DIFFRACTION (2.2 Å)