Georgios Skiniotis Lab

About the Skiniotis lab

Cell surface receptors are essential components of intracellular communication. These membrane-bound proteins transmit extracellular signals to the cell interior, responding to a variety of extracellular cues including light, small molecules and ions, peptides, lipids, and proteins. G protein-coupled receptors (GPCRs) are a large, diverse group of cell surface receptors essential for human physiology and, given their distinct signaling roles, make attractive targets for therapeutic interventions. Our lab is interested in elucidating the structural and mechanistic aspects of signal recognition and propagation by cell surface receptors, namely GPCRs and their interacting proteins.

In the news

St. Jude appoints leading scientist to create groundbreaking Center of Excellence for Structural Cell Biology

Our research summary

GPCR receptor signaling

G protein-coupled receptors (GPCRs) are a structurally conserved group of membrane proteins crucial for signal transduction in eukaryotes. Over 800 GPCRs have been identified in humans, each displaying specificity to a unique signal. Recognition of a cue by the extracellular side of a GPCR promotes conformational changes across the receptor to the intracellular side, inciting interactions with nearby G proteins. The activation of one G protein can have a cascade effect, modulating the production of hundreds of second messenger molecules that will spread the signal to the cell interior. As GPCRs are involved in controlling numerous crucial physiological processes, these receptors are attractive drug targets currently accounting for more than a third of approved therapeutic drugs.

We are interested in deciphering the mechanisms of signal transduction through detailing interactions between GPCRs and ligands, G protein subtypes, arrestins, and other effector complexes. Of particular interest are family C GPCRs, an exotic receptor group that includes crucial regulators of neurotransmission and systemic calcium levels. For example, we are keen on understanding how the calcium-sensing receptor (CaSR), a family C GPCR and master regulator of calcium homeostasis, instigates signaling. Our recent work has elucidated how CaSR undergoes conformational transitions in calcium binding that can drive the activation of distinct subtypes of G proteins.

We are also interested in structure-based ligand discovery initiatives aimed at characterizing the binding properties of small molecules and their effects on receptor structure and dynamics. This work lays the foundation for the development of next-generation ligands that may serve as potential efficacious therapeutics and highly specific tool compounds used to uncover biological mechanisms.

Our innovative approach

Our investigations employ primarily cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) to ascertain the 3D architecture and the dynamic behavior of macromolecular complexes. By coupling these powerful methodologies with molecular dynamics simulations, functional assays and other biophysical approaches, our team has made transformative discoveries that shape our understanding of GPCR signaling mechanisms.

Many of the high-resolution structures generated by our lab have come from in vitro experiments, but we are expanding our methodology to include cryo-ET to visualize GPCR signaling networks in situ, gathering a more physiologically accurate representation of these dynamic interactions. We are developing and optimizing cryo-ET workflows to view the spatial arrangements of GPCRs and other receptors in their native environment. Our exploration on this front and refinement of current structure-based approaches allows us to peek into complex biological questions in a unique manner.

Publications

Large library docking identifies positive allosteric modulators of the calcium-sensing receptor

Liu et al. Science, 2024

Time-resolved cryo-EM of G-protein activation by a GPCR

Papasergi-Scott et al. Nature, 2024

Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor

He et al. Nature, 2024

Insights into distinct signaling profiles of the µOR activated by diverse agonists

Qu et al. Nat Chem Biol, 2023

Structure determination of inactive-state GPCRs with a universal nanobody

Robertson et al. Nat Struct Mol Biol, 2022

The tethered peptide activation mechanism of adhesion GPCRs

Barros-Álvarez et al. Nature, 2022

The oxytocin signaling complex reveals a molecular switch for cation dependence

Meyerowitz et al. Nat Struct Mol Biol, 2022

Asymmetric activation of the calcium-sensing receptor homodimer

Gao et al. Nature, 2021

About Georgios Skiniotis

Dr. Skiniotis is a structural biologist who received his PhD from the European Molecular Biology Laboratory in Heidelberg, Germany. He trained as a postdoctoral fellow, focusing on structural biology and electron microscopy, at EMBL-Heidelberg before being named a Damon Runyon Cancer Research Foundation postdoctoral fellow and continuing his training at Harvard Medical School. In 2024, Dr. Skiniotis joined St. Jude as a Member in the Department of Structural Biology, an endowed chair of Structural Cell Biology and Founding Director of the Center of Excellence for Structural Cell Biology. His research employs structural approaches to understand the molecular mechanisms driving intracellular communication via transmembrane receptor signaling. Of particular interest is GPCRs and their partner proteins. Dr. Skiniotis employs a variety of structural approaches, such as cryo-electron microscopy and cryo-electron tomography, to study these proteins and their associated physiological processes.

Dr. Skiniotis has received numerous awards and honors, including the White House’s Presidential Early Career Award for Scientists and Engineers, the Earl and Thressa Stadtman Scholar Award and was named a Pew Scholar in biomedical sciences. He is also a valued contributor to the GPCR Collaborative, a St. Jude Research Collaborative designed to bring together global thought leaders to answer complex scientific questions with transformative potential.