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Procko, Erik Procko, Erik Gennis, Robert Jin, Hong Pogorelov, Taras Young, Heather J 2020-08-27T00:46:51Z 2020-08-27T00:46:51Z 2022-08-27T00:51:40Z 2020-02-27 2020-05 Neurotransmitter Sodium Symporters modulate neurotransmission and members of this family of transporters are a popular target in the treatment of depression, addiction, obsessive compulsive disorder, and generalized anxiety disorder including the serotonin transporter and the dopamine transporter. These transporters have been the targets of numerous mutagenesis studies, none so expansive as our deep mutational scans, where we have characterized the effects of every point mutant on the function and surface localization of two of these proteins, the serotonin transporter (SERT) and the dopamine transporter (DAT). Collaborating with Diwakar Shukla’s group at UIUC, we have further advanced the understanding of function in these transporters by performing molecular dynamics simulations with and without various substrates. These simulations support our deep mutagenesis conclusions, while yielding novel information about the binding characteristics of both the native and non-native substrates for the human serotonin transporter, a representative member of this symporter family. Work with SERT and DAT lead us to hypothesize that the conformational equilibria of the transport cycle in these transporters is affected differentially for substrate import by mutations which stabilize sampling one conformation over another. Using molecular dynamics, we have observed a third ion binding site previously unrecognized in this transporter. Further, we have effectively used deep mutational scanning in yeast to engineer increased receptor-ligand affinity utilizing the PDGF-B PDGFRß system. Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2022-05-01 The student, Heather Young, accepted the attached license on 2020-02-25 at 11:34. The student, Heather Young, submitted this Dissertation for approval on 2020-02-25 at 11:42. This Dissertation was approved for publication on 2020-02-27 at 16:22. DSpace SAF Submission Ingestion Package generated from Vireo submission #14878 on 2020-08-25 at 17:38:49 Made available in DSpace on 2020-08-27T00:46:51Z (GMT). No. of bitstreams: 2 YOUNG-DISSERTATION-2020.pdf: 17135993 bytes, checksum: 1971b1fb99d12368caed7dacd7b71906 (MD5) LICENSE.txt: 4210 bytes, checksum: 96ef25c8f972aed764ce02a55729bfbd (MD5) Previous issue date: 2020-02-27 Embargo set by: Seth Robbins for item 115838 Lift date: 2022-08-27T00:46:59Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 115838 Lift date: 2022-08-27T00:50:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 115838 Lift date: 2022-08-27T00:51:40Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system Author requested closed access (OA after 2yrs) in Vireo ETD system Limited application/pdf http://hdl.handle.net/2142/108225 en Copyright 2020 Heather J Young Serotonin Transporter Neurotransmitter Transporter PDGF SERT Dopamine Dopamine Transporter DAT Serotonin transporter import text Thesis Biochemistry Biochemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.