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. |
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•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]
secondary structure with two key residues in the activation loop (highlighted in light blue) for Ponatinab binding
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]
FGFR4 active site for ponatinib binding with involved residues labeled
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]
Quiz Question 1See AlsoCreditsIntroduction - Emily & Cory Overall Structure - Nicole & Connor Drug Binding Site - Julie & Cory Additional Features - Emily & Nicole Quiz Question 1 - Julie & Connor 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. | ||||||||||||
