Research

The Gati lab pursues a fundamental question at the intersection of structural biology and pharmacology: how do membrane proteins sense their environment and transduce signals across the cell membrane, and how can this knowledge be harnessed to develop better medicines? We focus on two of the most therapeutically important protein families in the human genome — G protein-coupled receptors (GPCRs) and solute carriers (SLCs). GPCRs mediate nearly every physiological process, from pain and mood to immune responses, and are the targets of roughly one-third of all approved drugs. SLCs govern the transport of neurotransmitters, metabolites, and ions, yet remain dramatically underexplored as drug targets despite their central roles in neurological and psychiatric disease. Understanding how these proteins work at atomic resolution is essential to designing therapeutics that are both effective and precise.

Our primary tool is single-particle cryo-electron microscopy (cryoEM), which allows us to visualize these proteins in near-native states and capture fleeting conformational intermediates that are invisible to classical structural methods. We pair this with a comprehensive suite of biochemical and biophysical approaches — including radioligand binding assays, receptor pharmacology, molecular dynamics simulations, and single-molecule biophysics — to connect static structures to dynamic function. This integrated approach has allowed us to determine the structural basis of GABA sensing by the metabotropic GABAB receptor, GABA reuptake inhibition through the transporter GAT1 and GAT3, uncover the molecular mechanisms of inverse agonism at the kappa-opioid receptor, resolve the activation architecture of complement receptors C3aR and C5aR1, and capture nucleotide-release intermediates at the mu-opioid receptor — work published in Nature, Nature Chemical Biology, Nature Communications, and Cell. Together, these studies are building a mechanistic framework for how GPCRs and SLCs couple ligand binding to downstream signaling, and how that coupling can be selectively tuned by small molecules.

Looking forward, the lab is expanding its efforts to map the full conformational landscapes of GPCRs, develop optopharmacological tools for spatiotemporal control of receptor activity, and expand our methodological toolbox towards in silico protein design, biophysical techniques, and drug discovery. We welcome collaborations with researchers interested in membrane protein structure determination, biophysical characterization, or structure-guided drug design.