Sandbox Reserved 425

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This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.

Contents 1 Fibroblast Growth Factor Receptor/Ponatinib (4uxq) 2 Introduction 3 Overall Structure 4 Binding Interactions 5 Additional Features 6 Quiz Question 1 7 See Also 8 Credits 9 References

Fibroblast Growth Factor Receptor/Ponatinib (4uxq)

by Julie Boshar, Emily Boyle, Nicole Kirby, Cory Thomas, Connor Walsh

Student Projects for UMass Chemistry 423 Spring 2016

Introduction

•Plays a role in a variety of cancers

•Ponatinib is a drug prescribed to patients with chronic myeloid leukemia and Philadelphia-chromosome positive active lymphoblastic leukemia. Although, it has recently shown side effects causing blood clots and narrowing blood vessels.

•FGFR plays a role in the signaling system with FGF by initiating signaling cascades that control development and tissue repair. The disruption of this signaling system is involved in tumor growth [3]

•While most inhibitors are selective for FGFR1-3 and show a reduced binding to FGFR4, Ponatinib binds to FGFR4 [3]

•Ponatinib is a Bcr-Abl tyrosine kinase inhibitor (TKI) [3]

spinqualitylabelsall models 4uxq, depiction of secondary structure elements Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Overall Structure

•Ligands: SO4, 0LI [C29 H27 F3 N6 O]

•Identical amino acid sequence to cI44 with the exception of 1 residue. [1]

spinqualitylabelsall models 4uxq, insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Binding Interactions

•Ponatinib binds to the "DFG-out" conformation of Bcr-Abl, where the Phe (F) is out of its hydrophobic pocket [3]

•To bind there must be a a conformational rearrangement of the conserved Asp630-Phe631-Gly632 (DFG) tripeptide motif at the proximal end of the activation loop [3]

spinqualitylabelsall models 4uxq, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Additional Features

• FGFR-4 is abundantly present in human prostate cancer

•Variant of FGFR-4 with (Arg(388)) replacing (Gly(388)) is associated with increased human prostate cancer. This causes increased receptor stability and activation. [2]

spinqualitylabelsall models pdbcode, Insert caption here Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Quiz Question 1

See Also

• Fibroblast growth factor receptor
• 4uxq
• 4v01
• 4v04
• 4v05

Credits

Introduction - name of team member

Overall Structure - name of team member

Drug Binding Site - name of team member

Additional Features - name of team member

Quiz Question 1 - name of team member

References

[1] Ron D, Reich R, Chedid M, Lengel C, Cohen OE, Chan AM, Neufeld G, Miki T, Tronick SR. Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor. J Biol Chem. 1993 Mar 15;268(8):5388-94. PMID:http://www.ncbi.nlm.nih.gov/pubmed/7680645

[2] Wang J, Yu W, Cai Y, Ren C, Ittmann MM. Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia. 2008 Aug;10(8):847-56. PMID: http://www.ncbi.nlm.nih.gov/pubmed/18670643

[3] Tucker, J. A.; Klein, T.; Breed, J.; Breeze, A. L.; Overman, R.; Phillips, C.; Norman, R. A. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure 2014, 22, 1764-1774.