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An SH2 domain model of STAT5 in complex with phospho-peptides define “STAT5 Binding Signatures”

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Abstract

The signal transducer and activator of transcription 5 (STAT5) is a member of the STAT family of proteins, implicated in cell growth and differentiation. STAT activation is regulated by phosphorylation of protein monomers at conserved tyrosine residues, followed by binding to phospho-peptide pockets and subsequent dimerization. STAT5 is implicated in the development of severe pathological conditions, including many cancer forms. However, nowadays a few STAT5 inhibitors are known, and only one crystal structure of the inactive STAT5 dimer is publicly available. With a view to enabling structure-based drug design, we have: (1) analyzed phospho-peptide binding pockets on SH2 domains of STAT5, STAT1 and STAT3; (2) generated a model of STAT5 bound to phospho-peptides; (3) assessed our model by docking against a class of known STAT5 inhibitors (Müller et al. in ChemBioChem 9:723–727, 2008); (4) used molecular dynamics simulations to optimize the molecular determinants responsible for binding and (5) proposed unique “Binding Signatures” of STAT5. Our results put in place the foundations to address STAT5 as a target for rational drug design, from sequence, structural and functional perspectives.

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Abbreviations

BLAST:

Basic local alignment search tool

FP:

Fluorescence polarization

IC50 :

Half maximal inhibitory concentration

MD:

Molecular dynamics

MM-GBSA:

Molecular mechanics-generalized born surface area

MSA:

Multiple sequence alignment

pY:

Tyrosine-phosphorylated

RMSD:

Root mean square deviation

SH2:

Src homology 2

STAT:

Signal transducer and activator of transcription

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Acknowledgments

The authors thank Dr. Vojislava Pophristic, Dr. Preston B. Moore and Dr. Elia Eschenazi for their help in useful discussions. Supercomputing time allocated to the project was generously provided (P. Kollman graduate student award) by the American Chemical Society (ACS) COMP division and the National Institute for Computational Sciences (NICS).

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  1. Eleonora Gianti

    Present address: Institute for Computational Molecular Science, Temple University, SERC Building, 1925 North 12th St, Philadelphia, PA, 19122, USA

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  1. Department of Chemistry and Biochemistry, University of the Sciences, 600 S. 43rd Street, Philadelphia, PA, 19104, USA

    Eleonora Gianti & Randy J. Zauhar

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  1. Eleonora Gianti
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Correspondence to Eleonora Gianti or Randy J. Zauhar.

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Gianti, E., Zauhar, R.J. An SH2 domain model of STAT5 in complex with phospho-peptides define “STAT5 Binding Signatures”. J Comput Aided Mol Des 29, 451–470 (2015). https://doi.org/10.1007/s10822-015-9835-6

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