Cornelius Gati

• PostDoc, Stanford University, 2017-2018
• PostDoc, MRC – Laboratory of Molecular Biology, 2016-2017

Summary Statement of Research Interests

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 reuptake inhibition through the transporter GAT1, 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.

Research Keywords

Structural biology, Membrane protein biology, GPCR, Neurotransmitter transporters, Synapse, CryoEM, X-ray crystallography, Biophysics

Journal Article

• Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. ELIFE. Vol. 9
• Structural basis of the activation of a metabotropic GABA receptor. NATURE. Vol. 584 (7820), pp. 298-+.
• Toward G protein-coupled receptor structure-based drug design using X-ray lasers. IUCRJ. Vol. 6, pp. 1106-1119.
• CryoEM Maps and Associated Data Submitted to the 2015/2016 EMDataBank Map Challenge. Zenodo. Vol. 1.1
• XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity. NATURE. Vol. 569 (7755), pp. 289-+.
• Structural basis of ligand recognition at the human MT1 melatonin receptor. NATURE. Vol. 569 (7755), pp. 284-+.
• Cryo-EM structure of the human neutral amino acid transporter ASCT2. NATURE STRUCTURAL & MOLECULAR BIOLOGY. Vol. 25 (6), pp. 515-+.
• Structural biology of G protein-coupled receptors: new opportunities from XFELs and cryoEM. CURRENT OPINION IN STRUCTURAL BIOLOGY. Vol. 51, pp. 44-52.
• The structural basis of proton driven zinc transport by ZntB. NATURE COMMUNICATIONS. Vol. 8
• Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand. NATURE COMMUNICATIONS. Vol. 8
• Atomic structure of granulin determined from native nanocrystalline granulovirus using an X-ray free-electron laser. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. Vol. 114 (9), pp. 2247-2252.
• Native phasing of x-ray free-electron laser data for a G protein-coupled receptor. SCIENCE ADVANCES. Vol. 2 (9)
• Lipidic cubic phase injector is a viable crystal delivery system for time-resolved serial crystallography. NATURE COMMUNICATIONS. Vol. 7
• Gene Portals: A Framework for Integrating Clinical, Functional, and Structural Evidence into Rare Disease Variant Classification. medRxiv : the preprint server for health sciences. PubMed Web Address
• Structural snapshots capture nucleotide release at the μ-opioid receptor. Nature. Vol. 648 (8094), pp. 755-763. PubMed Web Address
• Molecular basis of human GABA transporter 3 inhibition. Nature communications. Vol. 16 (1), pp. 3830. PubMed Web Address
• Molecular mechanisms of inverse agonism via κ-opioid receptor-G protein complexes. Nature chemical biology. Vol. 21 (7), pp. 1046-1057. PubMed Web Address
• An opioid efficacy switch for reversible optical control of peripheral analgesia. bioRxiv : the preprint server for biology. PubMed Web Address
• Molecular basis of anaphylatoxin binding, activation, and signaling bias at complement receptors. Cell. Vol. 186 (22), pp. 4956-4973.e21. PubMed Web Address
• Structural basis of GABA reuptake inhibition. Nature. Vol. 606 (7915), pp. 820-826. PubMed Web Address
• Structural basis of ligand recognition at the human MT(1) melatonin receptor. Nature. Vol. 569 (7755), pp. 284-288. PubMed Web Address