7NX3

Crystal structure of ALK in complex with Fab324

Summary for 7NX3

• Entry DOI: 10.2210/pdb7nx3/pdb
• Related: 7NWZ 7NX0 7NX1 7NX2 7NX4
• Descriptor: ALK tyrosine kinase receptor, Fab324 HeavyChain, Fab324 Light Chain, ... (4 entities in total)
• Functional Keywords: cell surface receptor cytokine binding, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 179638.22

Authors

De Munck, S.,Savvides, S.N. (deposition date: 2021-03-17, release date: 2021-10-27, Last modification date: 2024-10-09)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.81 Å)