7MZY

Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-986

Summary for 7MZY

• Entry DOI: 10.2210/pdb7mzy/pdb
• Related: 7MZW 7MZX 7MZZ 7N00
• Descriptor: ALK tyrosine kinase receptor, ACETATE ION (3 entities in total)
• Functional Keywords: anaplastic lymphoma kinase, receptor tyrosine kinases, rtk, fam150, ltk, de novo protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64697.35

Authors

Reshetnyak, A.V.,Sowaileh, M.,Miller, D.J.,Rossi, P.,Myasnikov, A.G.,Kalodimos, C.G. (deposition date: 2021-05-24, release date: 2021-11-24, Last modification date: 2021-12-15)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.5 Å)