Abstract: The present invention provides methods for designing agents such as ligands capable of binding to a Janus kinase (Jak), particularly a Jak2 JH2, and especially a JH2 V617F, screening methods for identifying agents such as ligands and small molecules capable of binding to the same, and computer assisted methods for designing and identifying such agents. Further, the present invention provides methods for treating myeloproliferative neoplasias (MPNs) along with agents such as ligands and small molecules identified or designed using the methods described.

Abstract: The determination and use of three dimensional structures of receptor protein tyrosine kinases and/or their ligands are described. One particular group of such structures includes three dimensional structures of the extracellular domain of RPTKs. The three dimensional structures of RPTKs can faciliate the design and identification of modulators of RPTK function. Other such structures can include of RPTK ligands, such as stem cell factor or a fragment thereof. Modulators of RPTK function can be used to treat diseases that are mediated by inappropriate RPTK activity.

Abstract: Crystals of the tyrosine kinase domain of cytoplasmic tyrosine kinases and receptor tyrosine kinases that undergo ligand-mediated receptor dimerization are provided. In particular, crystals of a mutant of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FLGK), alone and in complex with a non-hydrolyzable adenosine triphosphate analogue, are provided. Also provided are the high resolution three dimensional structures of crystalline FLGK, both alone and in co-complex with the adenosine triphosphate analogue, as determined by X-ray diffraction.

Abstract: The present invention is directed to methods for designing ligands capable of binding to the kinase domain of the insulin-like growth hormone-1 (IGF-1) receptor with high affinity. Upon binding, these ligands are capable of acting as modulators of IGF1 activity. IGF1 modulators designed or identified using the methods of the invention may serve to inhibit an IGF1 activity or may serve to increase or prolong an IGF1 activity. Further provided are screening methods for identifying small molecules capable of binding to the tyrosine kinase domain of the IGF-I receptor.

Abstract: Crystals of the tyrosine kinase domain of cytoplasmic tyrosine kinases and receptor tyrosine kinases that undergo ligand-mediated receptor dimerization are provided. In particular, crystals of a mutant of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FLGK), alone and in complex with a non-hydrolyzable adenosine triphosphate analogue, are provided. Also provided are the high resolution three dimensional structures of crystalline FLGK, both alone and in co-complex with the adenosine triphosphate analogue, as determined by X-ray diffraction.

Abstract: Crystals of the tyrosine kinase domain of cytoplasmic tyrosine kinases and receptor tyrosine kinases that undergo ligand-mediated receptor dimerization are provided. In particular, crystals of a mutant of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FLGK), alone and in complex with a non-hydrolyzable adenosine triphosphate analogue, are provided. Also provided are the high resolution three dimensional structures of crystalline FLGK, both alone and in co-complex with the adenosine triphosphate analogue, as determined by X-ray diffraction.