My laboratory focuses on applying integrated structural and biochemical approaches to elucidate the molecular basis of protein-protein interactions and protein-ligand/drug interactions that are relevant to human health and diseases. Armed with such knowledge, we then apply chemical and pharmacological approaches to develop therapeutic innovations. Currently, we are studying the following proteins:
Amyloid peptide-degrading proteases: Metalloproteases, insulin degrading enzyme (IDE) and presequence protease (PreP) degrade amyloid beta, a peptide vital for the progression of Alzheimer's disease. IDE is also involved in the clearance of insulin, amylin, and glucagon, pancreatic peptides for glucose homeostasis. PreP is involved in the clearance of mitochondrial importing presequence peptides, which are toxic to mitochondria. Our structures of human IDE in complex with its substrates elucidate the molecular basis of how IDE recognizes amyloidogenic peptides and offers a basis to explore IDE-based therapeutics in controlling cerebral amyloid beta accumulation and blood sugar levels. Our structures of human PreP reveal how PreP recognizes amyloid beta. Future directions in studying proteases that degrade amyloid peptides include exploration into the molecular basis in the regulation of catalysis of IDE, PreP, and other amyloid-peptide degrading proteases such as neprilysin and endothelin converting enzymes, discovery of small molecule activator and inhibitor leads, and protein engineering for therapies.
Chemokines: Inflammation is vital in the progression of many chronic human illnesses. Proinflammatory chemokines, e.g., CCL5 and CCL3, play key roles in modulating inflammation and consequently affect disease progression such as cancer and immunological disorders. In addition, CCR5, the CCL3 and CCL5 cognate receptor, is a co-receptor for HIV virus. Self-association and binding to extracellular glycan of chemokines are key regulatory steps in controlling chemokine functions. Our structural and biochemical analyses of CCL3 and CCL5 have elucidated the structural basis of CCL3 and CCL5 oligomerization and binding to glycosaminoglycan (GAG). Future directions include the elucidation of the molecular basis of how oligomerization and GAG binding regulates chemokine functions and the development of small molecules to modulate inflammation.
Bacterial toxins secreted by human bacterial pathogens: We study bacterial adenylyl cyclase toxins that are only active upon entering into target cells and are associated with cellular proteins that serve as the activator. These adenylyl cyclase toxins raise the intracellular cyclic AMP (cAMP) of their host cells to benefit bacterial propagation. We have studied three adenylyl cyclase toxins, edema factor (EF) secreted by bacteria that cause anthrax, CyaA secreted bacteria that cause whooping cough, and ExoY injected by Pseudomonas aeruginosa, an opportunistic pathogens for nosocomial infections. Both EF and CyaA bind the cellular calcium sensor, calmodulin, with high affinity. Our structural and biochemical analyses have elucidated how calmodulin binds and activates EF and CyaA. ExoY is activated by binding to F-actin and we show that ExoY induces the bundling of F-actin. We will continue to address the structural basis for the interaction of these toxins with their cellular partners. We will also explore the therapeutic potential of adenylyl cyclase toxins in human diseases as well. The incident of bioterrorism-related anthrax in 2001 has moved the challenge against anthrax from an obscure agricultural problem to the center of bio-defense. Given the ease of making antibiotic-resistant anthrax strains and unknown enemies, the best defense against anthrax is to build up a battery of possible antidotes against anthrax that can be rapidly scaled up for production in response to the low probability, high impact incidence of anthrax-related bioterrorism.
University of Texas Southwestern Medical School
Dallas, Texas
Postdoctoral fellow - Pharmacology
1993
University of Texas, Austin
Austin, Texas
PhD - Biological Sciences
1988
University of Texas Austin
Austin, Texas
Postdoctoral fellow - Virology
1988
Taiwanese Air Force
Taiwan
First Lieutenant
1984
National Taiwan University
Taipei, Taiwan
B.S. - Zoology
1982
Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states.
Structural analysis of Mycobacterium tuberculosis M13 metalloprotease Zmp1 open states. Structure. 2021 07 01; 29(7):709-720.e3.
PMID: 33378640
Pseudomonas aeruginosa exoenzyme Y directly bundles actin filaments.
Pseudomonas aeruginosa exoenzyme Y directly bundles actin filaments. J Biol Chem. 2020 03 13; 295(11):3506-3517.
PMID: 32019868
Reinvestigating the synthesis and efficacy of small benzimidazole derivatives as presequence protease enhancers.
Reinvestigating the synthesis and efficacy of small benzimidazole derivatives as presequence protease enhancers. Eur J Med Chem. 2019 Dec 15; 184:111746.
PMID: 31610373
Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening.
Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening. Eur J Med Chem. 2019 Oct 01; 179:557-566.
PMID: 31276900
Rapid Discovery and Characterization of Synthetic Neutralizing Antibodies against Anthrax Edema Toxin.
Rapid Discovery and Characterization of Synthetic Neutralizing Antibodies against Anthrax Edema Toxin. Biochemistry. 2019 07 09; 58(27):2996-3004.
PMID: 31243996
Catalytic Mechanism of Amyloid-ß Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation.
Catalytic Mechanism of Amyloid-ß Peptide Degradation by Insulin Degrading Enzyme: Insights from Quantum Mechanics and Molecular Mechanics Style Møller-Plesset Second Order Perturbation Theory Calculation. J Chem Inf Model. 2018 09 24; 58(9):1926-1934.
PMID: 30133282
Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme.
Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme. Elife. 2018 03 29; 7.
PMID: 29596046
Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination.
Locking the Elbow: Improved Antibody Fab Fragments as Chaperones for Structure Determination. J Mol Biol. 2018 02 02; 430(3):337-347.
PMID: 29273204
Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL. Oncotarget. 2016 Oct 18; 7(42):68833-68841.
PMID: 27626698
In vivo epidermal migration requires focal adhesion targeting of ACF7.
In vivo epidermal migration requires focal adhesion targeting of ACF7. Nat Commun. 2016 05 24; 7:11692.
PMID: 27216888
Established Investigator
American Heart Association
1999 - 2002
Young Investigator
Cancer Research Foundation
1995 - 1996
University fellowship
University of Texas, Austin
1983 - 1984