PDBsum entry 5iuh

Transferase

PDB id: 5iuh

Contents

Protein chain

285 a.a.

Ligands

34Y

Waters ×139

PDB id:

5iuh

Name:

Transferase

Title:

Crystal structure of the anaplastic lymphoma kinase (alk) in complex with 5d

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: unp residues 1084-1410. Synonym: anaplastic lymphoma kinase. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: alk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf21.

Resolution:

2.10Å R-factor: 0.183 R-free: 0.221

Authors:

C.H.Tu,S.Y.Wu

Key ref:

C.H.Tu et al. (2016). Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK). J Med Chem, 59, 3906-3919. PubMed id: 27031565 DOI: 10.1021/acs.jmedchem.6b00106

Date:

18-Mar-16 Release date: 18-May-16

Protein chain

Q9UM73  (ALK_HUMAN) -  ALK tyrosine kinase receptor from Homo sapiens

Seq: 1620 a.a.

Struc: 285 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acs.jmedchem.6b00106

J Med Chem 59:3906-3919 (2016)

PubMed id: 27031565

Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).

C.H.Tu, W.H.Lin, Y.H.Peng, T.Hsu, J.S.Wu, C.Y.Chang, C.T.Lu, P.C.Lyu, C.Shih, W.T.Jiaang, S.Y.Wu.

ABSTRACT

Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.