Lecture 17 -Receptors G-proteins

A heterotrimeric g-protein the basic structure(ras

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Unformatted text preview: A heterotrimeric G-protein The Basic Structure (Ras) The Basic Structure (G-protein) 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. Switch I Switch II Switch III Mechanism of Hydrolysis • General idea: – generate OH- to attack -phosphate – Have to neutralize the negative charge on the phosphate Model 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 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. What G-proteins can Do Source: Molecular Biology of the Cell, fourth ed. 2002 The G-protein Cycle •GTP form = active •GDP form = inactive • activated -subunit hydrolyzes GTP to GDP...
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A heterotrimeric G-protein The Basic Structure(Ras The...

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