PDBsum entry 4v01

Transferase

PDB id: 4v01

Contents

Protein chains

273 a.a.

Ligands

SO4 ×6

EDO ×10

0LI ×2

Waters ×277

PDB id:

4v01

Name:

Transferase

Title:

Fgfr1 in complex with ponatinib (co-crystallisation).

Structure:

Fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, pfeiffer syndrome), isoform cra_b. Chain: a, b. Fragment: kinase, unp residues 22-329. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.33Å R-factor: 0.191 R-free: 0.238

Authors:

J.Tucker,T.Klein,J.Breed,A.Breeze,R.Overman,C.Phillips,R.A.Norman

Key ref:

J.A.Tucker et al. (2014). Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure, 22, 1764-1774. PubMed id: 25465127 DOI: 10.1016/j.str.2014.09.019

Date:

10-Sep-14 Release date: 10-Dec-14

Protein chains

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

Seq: 822 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

DOI no: 10.1016/j.str.2014.09.019

Structure 22:1764-1774 (2014)

PubMed id: 25465127

Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4.

J.A.Tucker, T.Klein, J.Breed, A.L.Breeze, R.Overman, C.Phillips, R.A.Norman.

ABSTRACT

The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases has been implicated in a wide variety of cancers. Despite a high level of sequence homology in the ATP-binding site, the majority of reported inhibitors are selective for the FGFR1-3 isoforms and display much reduced potency toward FGFR4, an exception being the Bcr-Abl inhibitor ponatinib. Here we present the crystal structure of the FGFR4 kinase domain and show that both FGFR1 and FGFR4 kinase domains in complex with ponatinib adopt a DFG-out activation loop conformation. Comparison with the structure of FGFR1 in complex with the candidate drug AZD4547, combined with kinetic characterization of the binding of ponatinib and AZD4547 to FGFR1 and FGFR4, sheds light on the observed differences in selectivity profiles and provides a rationale for developing FGFR4-selective inhibitors.