PDBsum entry 5aab

Transferase

PDB id: 5aab

Contents

Protein chain

294 a.a.

Ligands

VGH

Waters ×192

PDB id:

5aab

Name:

Transferase

Title:

Structure of c1156y,l1198f mutant human anaplastic lymphoma kinase in complex with crizotinib

Structure:

Alk tyrosine kinase receptor. Chain: a. Fragment: tyrosine kinase domain, unp residues 1093-1411. Synonym: anaplastic lymphoma kinase. Engineered: yes. Mutation: yes. Other_details: nonphosphorylated

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.20Å R-factor: 0.211 R-free: 0.246

Authors:

M.Mctigue,Y.Deng,W.Liu,A.Brooun,A.Stewart

Key ref:

A.T.Shaw et al. (2016). Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med, 374, 54-61. PubMed id: 26698910 DOI: 10.1056/NEJMoa1508887

Date:

23-Jul-15 Release date: 08-Jun-16

Protein chain

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

Seq: 1620 a.a.

Struc: 294 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

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: 10.1056/NEJMoa1508887

N Engl J Med 374:54-61 (2016)

PubMed id: 26698910

Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.

A.T.Shaw, L.Friboulet, I.Leshchiner, J.F.Gainor, S.Bergqvist, A.Brooun, B.J.Burke, Y.L.Deng, W.Liu, L.Dardaei, R.L.Frias, K.R.Schultz, J.Logan, L.P.James, T.Smeal, S.Timofeevski, R.Katayama, A.J.Iafrate, L.Le, M.McTigue, G.Getz, T.W.Johnson, J.A.Engelman.

ABSTRACT

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).