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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) [1] 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) ^[1]

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

Student Projects for UMass Chemistry 423 Spring 2016

Introduction

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

•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^[2]

•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)^[4]

Overall Structure

•Ligands: SO4, 0LI [C29 H27 F3 N6 O]

•Identical amino acid sequence to cI44 with the exception of 1 residue.^[5]

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

spinqualitylabelsall models 4uxq, secondary structure with two key residues in the activation loop (highlighted in light blue) for Ponatinab binding 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^[6]

•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^[7]

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

spinqualitylabelsall models 4uxq, FGFR4 active site for ponatinib binding with involved residues labeled 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 - Emily & Cory

Overall Structure - Nicole & Connor

Drug Binding Site - Julie & Cory

Additional Features - Emily & Nicole

Quiz Question 1 - Julie & Connor

References

1. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
2. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
3. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
4. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
5. ↑ 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:7680645
6. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019
7. ↑ Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural Insights into FGFR Kinase Isoform Selectivity: Diverse Binding Modes of AZD4547 and Ponatinib in Complex with FGFR1 and FGFR4. Structure. 2014 Dec 2;22(12):1764-74. doi: 10.1016/j.str.2014.09.019. Epub 2014, Nov 20. PMID:25465127 doi:http://dx.doi.org/10.1016/j.str.2014.09.019

[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.