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Published byJaven Tier Modified over 9 years ago
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An investigation of the importance of the Kinase Hinge region on the structure and function of selected Tyrosine Kinases
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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
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c-Kit : key structural components
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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”
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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”
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Inactive form of c-Kit + Gleevec : juxtamembrane :green; P loop :magenta; C (control) –helix :cyan ; C (catalytic) loop :gray ; A (activation) loop: red
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Active form of c-Kit: blue ; Inactive form : yellow The molecular brake and the kinase hinge
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Induced fit of STI binding to c-Kit : 1T45 in yellow, 1T46 in gray
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The molecular brake and the kinase hinge
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Inactive c-Kit + STI(1T46)
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STI induces fit in molecular break Van der Waals surface detailing the binding pocket for 1T46 + STI ; Red : Ile 653
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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)
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Mechanism for release of the molecular brake through movement of Activation loop involves a similar interaction between Ile653 and Phe 811
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Tyrosine Kinases: c-Kit and c-Abl
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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
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Inhibition of c-Kit through the binding of ellipticines
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Inhibition of c-Abl through the binding of ellipticines : competitive inhibition HO-ellipticine: Blue MeO-ellipticene: green ADP: Cyan
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Inhibition of c-Kit through the binding of ellipticines ; OMe-Phe hydrophobic interaction stabilizing backbone h-bond
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