Inhibiting Smurf1: Biological and Mechanistic Approach

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dc.contributor.advisorStatsyuk, Alexander V.
dc.contributor.committeeMemberCuny, Gregory D.
dc.contributor.committeeMemberUdugamasooriya, D. Gomika
dc.contributor.committeeMemberŞen, Mehmet
dc.contributor.committeeMemberZastrow, Melissa L.
dc.creatorChuong, Patrick
dc.date.accessioned2023-01-01T23:20:54Z
dc.date.available2023-01-01T23:20:54Z
dc.date.createdAugust 2022
dc.date.issued2022-08
dc.date.updated2023-01-01T23:20:55Z
dc.description.abstractSmurf1 is an E3 ligase in the ubiquitin proteasome system that regulates bone degradation. Within the E3 ligase categories, Smurf1 is a HECT E3 ligase in the NEDD4 family that has been experimentally shown to be genetically microduplicated in patients suffering from osteoporosis. The deletion of Smurf1 in mice has proven to increase the volume of bone density in an age dependent manner. Therefore, it stands to reason that inhibition of Smurf1 via small molecules may be useful in osteoporosis therapy. Given the lack of crystal structure, not much is known about the structure of Smurf1, especially the HECT domain. To date there has been no published data on inhibitors specific to Smurf HECT domain. In the following body of work, we discuss two synthesized inhibitors that inhibit Smurf1 HECT domain and we begin to study its mechanism of action within the protein. We utilize a variety of assays such the traditional auto-ubiquitination assay as well as newer ubiquitin probes such as UbFluor and Ub-Propargylamine. Herein, we discuss potential binding sites for the two compounds through mutations and chimera proteins. Due to the lack of crystal structure, we have created homology models of the compounds against Smurf1 and will attempt to validate them in the future. Lastly, due to the nature of UbFluor, it provides the perfect avenue to be a reliable probe to run high throughput screens (HTS) against Smurf1. We compile a list of compounds that have exhibited potential to be tractable leads in the future.
dc.description.departmentPharmacological and Pharmaceutical Sciences, Department of
dc.format.digitalOriginborn digital
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10657/13269
dc.language.isoeng
dc.rightsThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).
dc.subjectUbiquitin
dc.subjectE3 Ligase
dc.subjectSmurf1
dc.subjectHECT
dc.titleInhibiting Smurf1: Biological and Mechanistic Approach
dc.type.dcmiText
dc.type.genreThesis
thesis.degree.collegeCollege of Pharmacy
thesis.degree.departmentPharmacological and Pharmaceutical Sciences, Department of
thesis.degree.disciplinePharmacology
thesis.degree.grantorUniversity of Houston
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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