7T6F

Structure of active Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain

7T6F の概要

• エントリーDOI: 10.2210/pdb7t6f/pdb
• EMDBエントリー: 25715
• 分子名称: Tyrosine-protein kinase, Interferon lambda receptor 1, ADENOSINE, ... (4 entities in total)
• 機能のキーワード: signaling complex, janus kinase, jak, oncogenic mutation, gain-of-function mutation, cytokine receptor, signaling protein
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 293233.32

構造登録者

Glassman, C.R.,Tsutsumi, N.,Jude, K.M.,Garcia, K.C. (登録日: 2021-12-13, 公開日: 2022-03-16, 最終更新日: 2024-02-28)

主引用文献

Glassman, C.R.,Tsutsumi, N.,Saxton, R.A.,Lupardus, P.J.,Jude, K.M.,Garcia, K.C.
Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation.
Science, 376:163-169, 2022

PubMed Abstract: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.

PubMed: 35271300
DOI: 10.1126/science.abn8933

実験手法

ELECTRON MICROSCOPY (3.6 Å)