An SH2 domain model of STAT5 in complex with phospho-peptides define "STAT5 Binding Signatures".
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.
Department of Chemistry and Biochemistry, University of the Sciences, 600 S. 43rd Street, Philadelphia, PA, 19104, USA, eleonora.gianti@gmail.com.
Eleonora
E
Gianti
Randy J
RJ
Zauhar
D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D050794:STAT1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D018909:src Homology Domains
D010748:Phosphopeptides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor