Hang (Hubert) Yin

Research Overview

I. Drug Discovery: identifying potential therapeutics that inhibit opioids-induced glial cell activation. Pain remains a significant public health issue with two-thirds of patients achieving little to no pain relief from the myriad of currently available pharmacotherapies and dosing regimens. The use of opioid (e.g. morphine) pharmacotherapies produces several rewarding and reinforcing side effects, which result in the drugs’ diversion to abuse settings. Glial cells have been found to play a critical role in initiating and maintaining increased nociception in response to peripheral nerve injury. The opioids-induced glial cell activation attenuates opioid-induced pain suppression and enhances the development of opioid tolerance and dependence, the drug reward, and other negative side effects such as respiratory depression. We are interested in employing structure-based drug design and high-throughput screening techniques to identify novel small-molecule inhibitors of the cell surface receptors that regulate glial cell activation. The identified agents will potentially serve as therapeutics that suppresses opioid-dependence and tolerance

II. Biotechnology Development: Protein engineering for regulating membrane protein-protein and protein-lipid interactions

Protein-Protein Interactions: Protein transmembrane domains regulate many pivotal biological processes, including cell signal transduction, cancer development, ion transmission, and membrane protein folding. However, the molecular recognition in membranes is little understood due to the lack of available probes with high affinity and specificity. Conventional tools such as antibodies are unable to bind to the transmembrane regions of membrane proteins. A second project in our lab is to develop exogenous peptide and small-molecule agents that target transmembrane helices. Using these agents, we can study these important membrane protein-protein interactions, thereby further our understanding of molecular recognition in membranes. As a proof-of-principle, we plan to develop novel peptide/peptidomimetic reagents to target the first transmembrane domain (TMD-1) of latent membrane proteins 1 (LMP-1) found on the Human herpesvirus. These designed peptides will be used to study TMD-1-mediated LMP-1 activation. The findings from these studies will lay the groundwork for the discovery of new pharmaceutical agents with which we can prevent, diagnose, and treat herpesvirus-dependent cancers.

Protein-Lipid Interactions: It is estimated that about 30% of the approximately 25,000 human genes code for membrane proteins. However, researchers have only determined the high resolution structures of a few hundred of those proteins. Membrane proteins usually are not water-soluble, so scientists must first use detergents to extract them from the phospholipid membrane before they can crystallize the protein. Yet when membrane proteins are freed from the native membrane environment, they behave erratically. This unruly behavior creates potential inaccuracies when one tries to build atomic-scale structures. Therefore devising a set of techniques that allows high-resolution structure determination of membrane proteins in their native environment would be transformative. Our goal is to develop an approach for structural investigation of membrane proteins based on self-assembled membrane polyhedra (MPP) reconstituted with the membrane protein of interest. Under the right conditions, lipid molecules can spontaneously self-assemble to form “supramolecular” clusters (Fig below, Panel A). Taking advantage of this self-assembly property, membrane proteins can be coaxed to form symmetrical, many-sided units, which facilitates the structural studies using x-ray crystallography (Panel B). The focus of our work is on improving the packing of membrane proteins in the MPP’s and controlling the MPP morphology using artificially designed peptides. Using in-silico mutations we attempt to optimize the binding affinities of the artificial peptides to membrane surfaces. In addition, computational studies also serve as an important guiding step in selecting specific lipids for constructing MPPs. Experiments on both lipid bilayers and liposomes of different sizes will be carried out to understand the curvature sensing and promoting tendencies of the designed peptides.