Post-translational modifications by the SUMO (Small Ubiquitin-like MOdifier) family of proteins are recently discovered essential regulatory mechanisms. During SUMO maturation, a family of SUMO-specific proteases known as SENPs is required for cleaving SUMO precursors. SENPs are also required for removal of SUMO modifications from target proteins. All SENPs in mammals are essential genes, and SENP1 has been shown to play an important role in prostate cancer development and angiogenesis. In preliminary studies, we also identified a role of SENP1 and SENP2 in HIV replication. The goal of this proposal is to improve our understanding of the structure and function of SENPs: their functions in the HIV life cycle, conformational changes and dynamics required for catalysis, and mechanism of inhibition by a group of small molecules. NMR studies in combination with site-directed mutagenesis and enzyme kinetic analysis, as well as molecular biological approaches will be used in these studies. Elucidation of the role of the conformational changes and dynamics required for the SENP catalytic cycle will be the first such study for this large class of enzymes that catalyzes the maturation of ubiquitin-like modifiers and removal of ubiquitin-like modifications. Insights obtained from the proposed studies will not only be fundamentally important for quantitative understanding of an important class of enzymes, but also necessary for rational design and improvement of their inhibitors to enable the development of innovative therapeutics for life-threatening diseases such as cancer and AIDS.

Public Health Relevance

The goal of this proposal is to improve our understanding of the structure and function of SENPs: their functions in the HIV life cycle, conformational changes and dynamics required for catalysis, and mechanism of inhibition by a group of small molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102538-03
Application #
8649059
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Sakalian, Michael
Project Start
2012-05-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$491,778
Indirect Cost
$199,053
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Chen, Chih-Hong; Namanja, Andrew T; Chen, Yuan (2014) Conformational flexibility and changes underlying activation of the SUMO-specific protease SENP1 by remote substrate binding. Nat Commun 5:4968
Madu, Ikenna G; Namanja, Andrew T; Su, Yang et al. (2013) Identification and characterization of a new chemotype of noncovalent SENP inhibitors. ACS Chem Biol 8:1435-41