PDBsum entry 4rwj

Transferase/transferase inhibitor

PDB id: 4rwj

Contents

Protein chains

307 a.a.

282 a.a.

Ligands

66T ×2

Waters ×87

PDB id:

4rwj

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of fgfr1 (c488a, c584s) in complex with azd4547 (n- {3-[2-(3,5-dimethoxyphenyl)ethyl]-1h-pyrazol-5-yl}-4-[(3r,5s)-3,5- dimethylpiperazin-1-yl]benzamide)

Structure:

Fibroblast growth factor receptor 1. Chain: a, b. Fragment: residues 458-765. Synonym: fgfr-1, basic fibroblast growth factor receptor 1, bfgfr, bfgf-r-1, fms-like tyrosine kinase 2, flt-2, n-sam, proto-oncogenE C- fgr. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bfgfr, cek, fgfbr, fgfr1, flg, flt2, hbgfr. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.49Å R-factor: 0.204 R-free: 0.250

Authors:

C.D.Sohl,K.S.Anderson

Key ref:

C.D.Sohl et al. (2015). Illuminating the molecular mechanisms of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles' heel of targeted therapy. Acs Chem Biol, 10, 1319-1329. PubMed id: 25686244 DOI: 10.1021/acschembio.5b00014

Date:

04-Dec-14 Release date: 22-Apr-15

Protein chain

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 307 a.a.*

Protein chain

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 282 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, B: 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/acschembio.5b00014

Acs Chem Biol 10:1319-1329 (2015)

PubMed id: 25686244

Illuminating the molecular mechanisms of tyrosine kinase inhibitor resistance for the FGFR1 gatekeeper mutation: the Achilles' heel of targeted therapy.

C.D.Sohl, M.R.Ryan, B.Luo, K.M.Frey, K.S.Anderson.

ABSTRACT

Human fibroblast growth factor receptors (FGFRs) 1-4 are a family of receptor tyrosine kinases that can serve as drivers of tumorigenesis. In particular, FGFR1 gene amplification has been implicated in squamous cell lung and breast cancers. Tyrosine kinase inhibitors (TKIs) targeting FGFR1, including AZD4547 and E3810 (Lucitanib), are currently in early phase clinical trials. Unfortunately, drug resistance limits the long-term success of TKIs, with mutations at the "gatekeeper" residue leading to tumor progression. Here we show the first structural and kinetic characterization of the FGFR1 gatekeeper mutation, V561M FGFR1. The V561M mutation confers a 38-fold increase in autophosphorylation achieved at least in part by a network of interacting residues forming a hydrophobic spine to stabilize the active conformation. Moreover, kinetic assays established that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. Structural analyses of these TKIs with wild type (WT) and gatekeeper mutant forms of FGFR1 offer clues to developing inhibitors that maintain potency against gatekeeper mutations. We show that AZD4547 affinity is preserved by V561M FGFR1 due to a flexible linker that allows multiple inhibitor binding modes. This is the first example of a TKI binding in distinct conformations to WT and gatekeeper mutant forms of FGFR, highlighting adaptable regions in both the inhibitor and binding pocket crucial for drug design. Exploiting inhibitor flexibility to overcome drug resistance has been a successful strategy for combatting diseases such as AIDS and may be an important approach for designing inhibitors effective against kinase gatekeeper mutations.