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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.
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