Lecture 17 -Receptors G-proteins

Switching states 3 main areas of g protein change

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Switching States 3 main areas of G-protein change conformation: – Switch I: Moves closer to Guanine when active, Thr177 H-bonds to the -phosphate of GTP – Switch II: -helix 2 rotates so G199 can H- bond to -phosphate, which pulls -strand 3 away from -strand 1 and toward -strand 2. This breaks old hydrogen bonds and makes new ones. – Switch III: interacts with switch II which propagates its structural changes to it.
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Switch I
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Switch II
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Switch III
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Mechanism of Hydrolysis General idea: generate OH - to attack -phosphate – Have to neutralize the negative charge on the phosphate
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Model
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The odd case of Ras Ras lacks the Arg that stabilizes the negative charge on the phosphate! Ras is very very slow at hydrolyzing GTP—is this why? Ras GTPase activating protein (GAP) supplies the necessary Arg residue and speeds up the reaction nearly 100,000 fold
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Why is all this important? Ras is a signalling molecule activated by various receptors in different pathways, including cell growth signals. Ras is mutated in 25% of human tumors – Mutations inactivate the GTP hydrolysis step, thereby keeping Ras switched “on”—and thus Ras keeps on stimulating cells to divide.