Identification of potent selective inhibitors and crystal structures of PTPs

Title
Identification of potent selective inhibitors and crystal structures of PTPs
Author
Hyun Yeol RYU
Alternative Author(s)
류현열
Advisor(s)
류성언
Issue Date
2019-02
Publisher
한양대학교
Degree
Master
Abstract
Protein tyrosine phosphatases (PTPs) are crucial enzymes that regulate cellular protein phosphorylation levels by counteracting the activity of protein tyrosine kinases (PTKs). Dysregulation of PTPs causes many diseases, such as cancer, diabetes, and neural and autoimmune disorders. They are also associated with various cell functions, such as cell differentiation, proliferation, immune system, and metabolism. Recently, many studies have investigated the treatment of PTP-related diseases
however, no drugs targeting PTPs have been successfully developed. Therefore, PTPs are regarded as valuable drug targets. Here, I identified selective inhibitors for PTPs, the most efficacious being PTP1B. These chemicals remarkably reduce enzyme activity, as indicated by their low IC50 values and have selectivity for specific PTPs. Protein tyrosine phosphatase 1B (PTP1B) is a regulator of the insulin signaling pathway and is related to type 2 diabetes, obesity, and breast cancer. Furthermore, PTP1B mutations are highly recurrent in the molecularly-related B cell lymphoma and Hodgkin’s lymphoma. The reduced phosphatase activity of PTP1B mutants leads to increased phosphorylation of JAK-STAT pathway proteins, which results in lymphoma. I sought to identify how drugs can regulate the activity of PTP1B and verify the structural and functional differences of PTP1B mutations compared to wild-type PTP1B. I used X-ray crystallography to determine the crystal structures of a PTP1B:inhibitor complex (1–321 residues) and PTP1B mutants (M74L, M282L, V184D, 1–321 residues). The PTP1B-inhibitor complex shows an initial electron density map of the inhibitor binding site, which provides important details about how the inhibitor controls enzyme activity. Finally, the structure of the PTP1B V184D mutant suggests that the mutation likely affects the conformation and activity of the enzyme.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000108108http://repository.hanyang.ac.kr/handle/20.500.11754/99326
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIOENGINEERING(생명공학과) > Theses (Master)
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