Collections > UNC Chapel Hill Undergraduate Honors Theses Collection > Design of photoactivatable inhibitors for spatiotemporal control of GEF activity
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Design of photoactivatable inhibitors for spatiotemporal control of GEF activity

  • File Type: pdf
  • | Filesize: 3.3 MB
  • Date Deposited: 2018-04-30
  • Date Created: 2018-05-01

Path:  Collections > UNC Chapel Hill Undergraduate Honors Theses Collection > Design of photoactivatable inhibitors for spatiotemporal control of GEF activity

Protein design methods have been applied to engineer novel protein folds, enzymes, and materials with atomic-level accuracy. However, little work has been done to apply it to engineer novel proteins that can be used in vivo to dissect biological processes. Here we utilize protein design to study the cellular signaling involved in cell motility. Cell motility is driven by the reorganization of the cytoskeleton, a process regulated by the Rho protein family of small GTPases. These molecules are activated at precise subcellular locations by guanine exchange factors (GEFs) with fine temporal control. Understanding the biological role of these molecules requires their investigation at the subcellular level in living cells. To this end, we developed photoactivatable GEF inhibitors to allow for the spatio-temporal control of these GTPases. The GEFs targeted in this work were GEF-H1 and the members of Vav family GEFs, specifically Vav2. The two serve orthogonal roles in cell motility, where GEF-H1 has GEF activity towards RhoA at the retracting edge, Vav targets Rac1 at the leading edge. Our computational work generated alibrary of GEF-H1 inhibitors, and two experimentally validated inhibitors for the Vav family displaying high specificity in silico.

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