6NG0

Crystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with sunitinib in the inactive state.

6NG0 の概要

• エントリーDOI: 10.2210/pdb6ng0/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbo xamide (3 entities in total)
• 機能のキーワード: kinase, 3d domain swap, inactive state, 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: 69806.72

構造登録者

Johnson, E.,McTigue, M.,Cronin, C.N. (登録日: 2018-12-21, 公開日: 2019-05-01, 最終更新日: 2024-03-13)

主引用文献

Johnson, E.,McTigue, M.,Gallego, R.A.,Johnson, T.W.,Timofeevski, S.,Maestre, M.,Fisher, T.S.,Kania, R.,Sawasdikosol, S.,Burakoff, S.,Cronin, C.N.
Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation.
J.Biol.Chem., 294:9029-9036, 2019

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a Ser/Thr kinase that operates via the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways to dampen the T-cell response and antitumor immunity. Accordingly, selective HPK1 inhibition is considered a means to enhance antitumor immunity. Sunitinib, a multi-receptor tyrosine kinase (RTK) inhibitor approved for the management of gastrointestinal stromal tumors (GISTs), renal cell carcinoma (RCC), and pancreatic cancer, has been reported to inhibit HPK1 In this report, we describe the crystal structures of the native HPK1 kinase domain in both nonphosphorylated and doubly phosphorylated states, in addition to a double phosphomimetic mutant (T165E,S171E), each complexed with sunitinib at 2.17-3.00-Å resolutions. The native nonphosphorylated cocrystal structure revealed an inactive dimer in which the activation loop of each monomer partially occupies the ATP- and substrate-binding sites of the partner monomer. In contrast, the structure of the protein with a doubly phosphorylated activation loop exhibited an active kinase conformation with a greatly reduced monomer-monomer interface. Conversely, the phosphomimetic mutant cocrystal structure disclosed an alternative arrangement in which the activation loops are in an extended domain-swapped configuration. These structural results indicate that HPK1 is a highly dynamic kinase that undergoes trans-regulation via dimer formation and extensive intramolecular and intermolecular remodeling of the activation segment.

PubMed: 31018963
DOI: 10.1074/jbc.AC119.007466

実験手法

X-RAY DIFFRACTION (2.05 Å)