NMR backbone assignments of the tyrosine kinase domain of human fibroblast growth factor receptor 3 in apo state and in complex with inhibitor PD173074

Domenico Sanfelice,Tom D Bunney,Brendan Farrell,Hans Koss,Alexander L Breeze,Matilda Katan,Gary S Thompson

doi:10.1007/s12104-018-9814-7

Abstract

Fibroblast growth factors receptors (FGFR) are transmembrane protein tyrosine kinases involved in many cellular process, including growth, differentiation and angiogenesis. Dysregulation of FGFR enzymatic activity is associated with developmental disorders and cancers; therefore FGFRs have become attractive targets for drug discovery, with a number of agents in late-stage clinical trials. Here, we present the backbone resonance assignments of FGFR3 tyrosine kinase domain in the ligand-free form and in complex with the canonical FGFR kinase inhibitor PD173074. Analysis of chemical shift changes upon inhibitor binding highlights a characteristic pattern of allosteric network perturbations that is of relevance for future drug discovery activities aimed at development of conformationally-selective FGFR inhibitors.

Highlights

Four fibroblast growth factors receptors (FGFR1–4) are known to interact with several FGFs (22) to regulate critical cellular processes (Beenken and Mohammadi 2009; Brooks et al 2012)
We present the backbone amide NMR resonance assignments for FGFR3 kinase domain in ligand-free and PD-bound states
FGFR3 was injected on a 5 mL HiTrap Q (GE Healthcare, Amersham, UK) equilibrated in Q Buffer A (25 mM Tris–HCl, 20 mM NaCl, 1 mM TCEP, pH 8.0)

Summary

Introduction

Four fibroblast growth factors receptors (FGFR1–4) are known to interact with several FGFs (22) to regulate critical cellular processes (Beenken and Mohammadi 2009; Brooks et al 2012). Keywords Fibroblast growth factor receptor 3 · Tyrosine kinase inhibitor · NMR resonance assignment · Cancer · Angiogenesis We present the backbone amide NMR resonance assignments for FGFR3 kinase domain in ligand-free and PD-bound states.

Results

Conclusion