Ruan Research

The Ruan Lab is part of the Department of Biochemistry & Molecular Biology at Sidney Kimmel Medical College, Thomas Jefferson University. Our lab studies the molecular mechanisms of membrane receptors and channels that facilitate cellular signal transduction using a combination of computational, structural, and biochemical techniques.

The overarching goal of the lab is to understand the allosteric communication that enables proteins to react to input signals precisely and how pharmacological compounds impact this process.

Past breakthroughs from Dr. Ruan have elucidated the activation mechanism of epidermal growth factor receptor kinases (EGFR), the gating and pharmacological principals of the pannexin 1 (PANX1) channel, the proton-activated chloride (PAC) channel, and the transient receptor potential melastatin (TRPM) 5 channel.

Proteins play an integral role in virtually every biological process, and their function is directly influenced by their unique structure. Determining the structure of proteins is crucial for understanding protein function at both normal and disease conditions. Cryo-electron microscopy (cryo-EM) is a cutting-edge alternative to X-ray crystallography, and obviates the need for crystal formation. Cryo-EM has made significant strides in recent times with improvements in electron detection and image processing, resulting in resolutions that are comparable to X-ray crystallography. Our objective is to leverage cryo-EM to ascertain high-resolution structures of significant membrane protein complexes that participate in cellular signaling, including cellular receptors and ion channels. Additionally, we combine structural methods with functional investigations to elucidate the relationship between structure and function of these membrane proteins.

A major portion of the transmembrane protein carries signaling functions by sensing external cues and initiate intracellular signaling cascades. In particular, receptor tyrosine kinases and receptor serine/threonine kinases are major players for fulfilling this function in eukaryotic cells. Although these molecules play crucial roles in regulating physiological functions and are extensively implicated in human diseases, we currently lack a detailed atomic-level understanding of these intricate molecular machines. This knowledge gap primarily stems from the inherent flexibility of the single-pass transmembrane domain, which poses significant challenges for structural analysis of these kinase receptors. In this research direction, we aim to comprehensively characterize these proteins using structural, functional, and computational approaches. In particular, we want to answer the following three questions:

1. How does kinase receptor recognize different extracellular cues and multimerize into a signaling-competent form?
2. How is kinase domain activation coupled with extracellular ligand stimulation?
3. How do disease-related mutations alter the normal function of these receptors?

By addressing these critical questions, we aspire to gain insights into the diseases associated with these receptors and provide valuable information for the development of therapeutic strategies to combat these debilitating conditions.