PDBsum entry 4fny

Transferase/inhibitor

PDB id: 4fny

Contents

Protein chain

273 a.a.

Ligands

I3K

Waters ×67

PDB id:

4fny

Name:

Transferase/inhibitor

Title:

Crystal structure of the r1275q anaplastic lymphoma kinase catalytic domain in complex with a benzoxazole inhibitor

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: kinase domain, 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.

Resolution:

2.45Å R-factor: 0.196 R-free: 0.252

Authors:

D.A.Whittington,L.F.Epstein,H.Chen

Key ref:

L.F.Epstein et al. (2012). The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase. J Biol Chem, 287, 37447-37457. PubMed id: 22932897

Date:

20-Jun-12 Release date: 29-Aug-12

Protein chain

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

Seq: 1620 a.a.

Struc: 273 a.a.

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

J Biol Chem 287:37447-37457 (2012)

PubMed id: 22932897

The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase.

L.F.Epstein, H.Chen, R.Emkey, D.A.Whittington.

ABSTRACT

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that, when genetically altered by mutation, amplification, chromosomal translocation or inversion, has been shown to play an oncogenic role in certain cancers. Small molecule inhibitors targeting the kinase activity of ALK have proven to be effective therapies in certain ALK-driven malignancies and one such inhibitor, crizotinib, is now approved for the treatment of EML4-ALK-driven, non-small cell lung cancer. In neuroblastoma, activating point mutations in the ALK kinase domain can drive disease progression, with the two most common mutations being F1174L and R1275Q. We report here crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations. Also included are crystal structures of ALK in complex with novel small molecule ALK inhibitors, including a classic type II inhibitor, that stabilize previously unobserved conformations of the ALK activation loop. Collectively, these structures illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R1275Q mutation. The novel active site topologies presented here may also aid the structure-based drug design of a new generation of ALK inhibitors.