An investigation of the importance of the Kinase Hinge region on the structure and function of selected Tyrosine Kinases c Kit active in blue inactive in yellow Activation involves a 6 7 degree tilt on the N lobe towards the C lobe N lobe C lobe c Kit key structural components Active form of c Kit juxtamembrane green P loop magenta C control helix cyan C catalytic loop gray A activation loop red C Glu is in DFG Phe is in Inactive form of c Kit juxtamembrane green P loop magenta C control helix cyan C catalytic loop gray A activation loop red C Glu is in DFG Phe is out Inactive form of c Kit Gleevec juxtamembrane green P loop magenta C control helix cyan C catalytic loop gray A activation loop red Active form of c Kit blue Inactive form yellow The molecular brake and the kinase hinge Induced fit of STI binding to c Kit 1T45 in yellow 1T46 in gray The molecular brake and the kinase hinge Inactive c Kit STI 1T46 STI induces fit in molecular break Van der Waals surface detailing the binding pocket for 1T46 STI Red Ile 653 STI induces fit in molecular break Solvent accessible surface for Inactive c Kit STI 1T46 Solvent accessible surface for Modified c Kit 1T46 brake on STI Mechanism for release of the molecular brake through movement of Activation loop involves a similar interaction between Ile653 and Phe 811 Phylogenetic Tree of Human Tyrosine Kinases NEK EK K fes fer matk csk frk fgr fyn yes src blk lyn hck lck srms ptk6 btk bmx itk tec txk abl2 abl1 epha8 ephb4 ephb3 ephb2 ephb1 epha7 epha6 epha4 epha5 epha3 epha2 epha1 epha zap 70 syk fak2 fak1 tnk1 ack1 jak3 jak2 tyk2 jak1 erbb3 erbb4 erbb2 erbb1 itk alk ros1 insrr igf1r insr aatk ptk7 ddr2 ddr1 ror2 ror1 musk ntrk3 ntrk2 ntrk1 ryk ron met tyro3 axl mertk tek tie ret fgfr4 fgfr3 fgfr2 fgfr1 vegfr3 vegfr2 vegfr1 pdgfrb pdgfra csf1rflt3 ckit FES CSK SRC BRK TEC ABL EPH SYK FAK ACK JAK EGFR ALK ROS INSR aatyk AATYK PTK7 DDR ROR MUSK TRK RYK MET UFO TIE RET FGFR VEGFR PDGFR Tyrosine Kinases c Kit and c Abl No such interaction is present in abl since no h bond stabilization is needed molecular brake is off for hinge region of Inactive abl STI 1OPJ Leu 317 in abl compared to Ile 653 in c Kit Gln 319 in abl compared to Asn 655 in c Kit Inhibition of c Kit through the binding of ellipticines Inhibition of c Abl through the binding of ellipticines competitive inhibition HO ellipticine Blue MeO ellipticene green ADP Cyan Inhibition of c Kit through the binding of ellipticines OMe Phe hydrophobic interaction stabilizing backbone h bond