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Lecture 4 Slide 72 ATM is a central molecule Have mutation in gene, can?t repair all of the DNA damage attacks chromosome aberrations Lecture 5 Slide 3 Last 5 years, less drugs approved by FDA for use bc of toxicity issues Recombinant proteins, antibodies Slide 4 Know names of drugs and targets Slide 5 Very small molecule- vitamin D, estrogen (steroids) Small hydrophobic Bind to intracellular receptor- nuclear receptors- gene transcription in nucleus Slide 8 All receptors on membrane Involves some way to affect target gene Good targets for pharm companies- antagonist, agonist, monoclonal antagonist Slide 7 and 9 Go together External signals active receptor Transfuse signal Activated by ATP- activated by kinase action Can go into nucleus and induce gene transcription/expression Slide 12 Want to be able to turn off transcription Add phospho group to activate. Remove to deactivate Proteins recognized by ubiquitin- cleans up proteins not needed in cells Degraded Slide 13 One of the largest groups of receptors Has 7 transmembrane domains Slide 15 Similar to G protein Only has 1 single transmembrane domain Slide 17 2 receptors Ligand binding sites 2 receptors come together to make a pocket- ligand binds Kinase aren?t activated Intracellular kinase (JAK)- proximity is important in activation step JAK kinases autophsophorylates Slide 18 SH domain can recognize phospho group activate stat NLS can translocalize into nucleus Slide 24 Several receptors Substrate specificity Slide 25 2 transmembrane domains- one with 12, one with 7 proteins Slide 26 SHH- humans Slide 27 Without hedgehog, 2 receptors side by side Smo always attached to Psc Downstream signaling Cos2 and Fu bound to microtubules Ci75 can go into nucleus but is transcription repressor Smo activated Works on releasing complex from microtubules phoshphorylation Ci75 is now activator Important in embryonic development As adult, shouldn?t be activated In cancer patients, hedgehog is abnormally activated Slide 29 Important for embryonic development Slide 32 Receptor and ligand from 2 differennt cells Intracellular molecule can translocolize into nucleus Slide 33 Notch signaling for stem cells Early neuronal development Notch and Delta are transmembrane proteins Slide 36 Use phosphatase- remove phospho group SHP1- removes group. Or degrade protein via ubiquitin Slide 37 Need a lot of blood for endurance sports Constant active stage of receptor Slide 40 Doesn?t need ligand if mutated Slide 41 Overexpression of abnormal receptors