7NX0

LTK:ALKAL1 complex stabilized by a Nanobody

7NX0 の概要

• エントリーDOI: 10.2210/pdb7nx0/pdb
• 関連するPDBエントリー: 7NWZ 7NX1 7NX2 7NX3 7NX4
• 分子名称: Leukocyte tyrosine kinase receptor, Nb3.16, ALK and LTK ligand 1, ... (5 entities in total)
• 機能のキーワード: cell surface receptor cytokine binding cytokine receptor complex, protein binding
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 100657.02

構造登録者

De Munck, S.,Savvides, S.N. (登録日: 2021-03-17, 公開日: 2021-10-27, 最終更新日: 2024-11-06)

主引用文献

De Munck, S.,Provost, M.,Kurikawa, M.,Omori, I.,Mukohyama, J.,Felix, J.,Bloch, Y.,Abdel-Wahab, O.,Bazan, J.F.,Yoshimi, A.,Savvides, S.N.
Structural basis of cytokine-mediated activation of ALK family receptors.
Nature, 600:143-147, 2021

PubMed Abstract: Anaplastic lymphoma kinase (ALK) and the related leukocyte tyrosine kinase (LTK) are recently deorphanized receptor tyrosine kinases. Together with their activating cytokines, ALKAL1 and ALKAL2 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development, cancer and autoimmune diseases. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain, consistent with a metabolic role for Drosophila ALK. Despite such functional pleiotropy and growing therapeutic relevance, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.

PubMed: 34646012
DOI: 10.1038/s41586-021-03959-5

実験手法

X-RAY DIFFRACTION (1.95 Å)