7MZX

AUGalpha - FAM150B - ALKL2 77-152

7MZX の概要

• エントリーDOI: 10.2210/pdb7mzx/pdb
• 関連するPDBエントリー: 7MZW 7MZX 7MZY 7MZZ 7N00
• NMR情報: BMRB: 30911
• 分子名称: ALK and LTK ligand 2 (1 entity in total)
• 機能のキーワード: anaplastic lymphoma kinase activating ligand, fam150b, alkl2 77-152, cytokine
• 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: 9007.61

構造登録者

Rossi, P.,Sowaileh, M.,Reshetnyak, A.V.,Kalodimos, C.G. (登録日: 2021-05-24, 公開日: 2021-11-24, 最終更新日: 2024-10-23)

主引用文献

Reshetnyak, A.V.,Rossi, P.,Myasnikov, A.G.,Sowaileh, M.,Mohanty, J.,Nourse, A.,Miller, D.J.,Lax, I.,Schlessinger, J.,Kalodimos, C.G.
Mechanism for the activation of the anaplastic lymphoma kinase receptor.
Nature, 600:153-157, 2021

PubMed Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.

PubMed: 34819673
DOI: 10.1038/s41586-021-04140-8

実験手法

SOLUTION NMR