Cheng Zhang Laboratory
Research Overview
Cellular function is tightly regulated by cell-surface receptors, many of which are integral membrane proteins containing one or more transmembrane helices. These receptors sense diverse extracellular signals, including hormones, peptides, lipids, ions, and membrane-tethered ligands, to transmit chemical signaling across the cell membrane and initiate complex intracellular signaling pathways. My research program focuses on understanding the mechanisms that govern receptor function and regulation, with a particular emphasis on G protein-coupled receptors (GPCRs) involved in immune and neuronal activity. Our laboratory integrates cryo-electron microscopy, cell-based pharmacology, and computational biology to define the molecular basis of GPCR activation, allosteric modulation, and signaling. A central goal of our work is to understand how receptor structure encodes signaling outcomes, and how ligand chemistry and binding modes shape receptor conformational states.
Building on these structural insights, we pursue structure-based drug design (SBDD) in close collaboration with computational biology groups, leveraging structure-guided virtual screening to identify small-molecule ligands for orphan and understudied GPCRs. In parallel, we seek to define non-canonical and previously unrecognized modes of receptor allosteric modulation, particularly in neuronal GPCRs, and to develop novel allosteric modulators through binding-based screening approaches. We also aim to uncover new metabolite-GPCR signaling pathways using structure-guided strategies. Collectively, this work is directed toward illuminating the understudied chemical and functional landscape of the GPCR superfamily, the “dark matter” of the human GPCRome.
Overall, my research program follow a trajectory from fundamental mechanistic investigation to the exploration of under-characterized regulatory and chemical space. By bridging structural biology, computational biology, and pharmacology, our laboratory seeks to generate new mechanistic insights, chemical tools, and therapeutic candidates targeting immune and neuronal GPCRs.
Our funding support is provided by NIGMS, NCI, NIAID, and NIDA from the NIH and biotech companies.