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J am chem soc 2013 135 12 pp 47884798 pka cataly5c

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Unformatted text preview: physiological action of hormones through the action of protein kinase A R=regulatory subunit C=catalytic subunit Lecture 4 Pharm Sci/Chem 177, University of California, Irvine Kinase Anatomy: PKA N- lobe Gly- rich loop αC helix Ac5va5on loop C- lobe Chemical Steps Captured in Crystals of Protein Kinase A Before phosphotransfer Par5al phosphotransfer Complete phosphotransfer Bas5das et al. J. Am. Chem. Soc., 2013, 135 (12), pp 4788–4798 PKA Cataly5c Cycle Fast Open Slow Fast Slow Fast Closed ? Slow Fast Fast In vitro vs. in vivo •  In cells, is the pre- steady- state kine5cs or steady- state kine5cs more relevant? •  Would cellular potency be expected to depend more on a drug’s: –  Binding affinity (Kd) –  on- rate –  off- rate ? •  ATP bound •  Ac5va5on loop (DFG- loop) in ac5ve conforma5on •  αC helix in proper place: –  Salt bridge to cataly5c lysine K72 –  Interac5on with ac4va4on loop (usually phosphorylated) N- lobe C- lobe αC helix One Ac5ve Conforma5on to Rule Them All …but different inac5ve conforma5ons. Some5mes other domains in the same protein or other proteins will trap the kinase in an inac5ve conforma5on...
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