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Cs27: Catalysis V. Trimeric G-proteins: Incomplete, defective enzymes and signaling

Cs27: Catalysis V. Trimeric G-proteins: Incomplete, defective enzymes and signaling. Biochemistry 655 26 October 2009. Goals. The ultimate fragmentation of the enzymatic cycle… Irreversibility: D G hydrolysis = -7 Kcal/mole! Catalysis involves three fundamental steps -

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Cs27: Catalysis V. Trimeric G-proteins: Incomplete, defective enzymes and signaling

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  1. Cs27: Catalysis V. Trimeric G-proteins: Incomplete, defective enzymes and signaling Biochemistry 655 26 October 2009

  2. Goals • The ultimate fragmentation of the enzymatic cycle… • Irreversibility: DGhydrolysis = -7 Kcal/mole! • Catalysis involves three fundamental steps - • Induced-fit, catalysis, product release are forced to occur separately • Recruiting and exploiting Gaps and Gefs • …makes a molecular transistor • Survey the active site of Ras GTPase • GTP hydrolysis as phosphoryl transfer • Associative, dissociative transition states • A “requirement” for arginine • Respecting the fragmentation of the enzymatic cycle solved a problem in structural biology • Aluminum tri(tetra) fluoride as a transition-state analog • Crystallizing the transition state analog complex

  3. NH NH2 C d- NH2 d- d- d- d- d- Associative (SN2) vs Dissociative (SN1) transition states O O Associative (mimicked by Al4; Stabilized by Arg) Pg O OH2 Pb O O O Pg Dissociative (not mimicked by Al4; Nor s.tabilized by Arg) O OH2 Pb O

  4. Induced-fit Product release Catalysis The enzymatic cycle and transmembrane communication GEF (exchange) GAP(activation)

  5. A Molecular transistor? GEF GEF GAP GAP Target Amplified signal …as a switch …as an amplifier

  6. P-loop Switch 2 Switch 1 G-protein architecture: switch regions

  7. DATA Phases Refinement

  8. GTPgS:Mg++ Heterotrimer complex a1GDP

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