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

• Sierra, R. G., Gati, C., Laksmono, H., Dao, E. H., Gul, S., Fuller, F., Kern, J., Chatterjee, R., Ibrahim, M., Brewster, A. S., Young, I. D., Michels-Clark, T., Aquila, A., Liang, M., Hunter, M. S., Koglin, J. E., Boutet, S., Junco, E. A., Hayes, B., Bogan, M. J., Hampton, C. Y., Puglisi, E. V., Sauter, N. K., Stan, C. A., Zouni, A., Yano, J., Yachandra, V. K., Soltis, S. M., Puglisi, J. D., DeMirci, H. (2016). Concentric-flow electrokinetic injector enables serial crystallography of ribosome and photosystem II. Nature methods. Vol. 13 (1), pp. 59-62. PubMed Web Address
• Li, D., Stansfeld, P. J., Sansom, M. S., Keogh, A., Vogeley, L., Howe, N., Lyons, J. A., Aragao, D., Fromme, P., Fromme, R., Basu, S., Grotjohann, I., Kupitz, C., Rendek, K., Weierstall, U., Zatsepin, N. A., Cherezov, V., Liu, W., Bandaru, S., English, N. J., Gati, C., Barty, A., Yefanov, O., Chapman, H. N., Diederichs, K., Messerschmidt, M., Boutet, S., Williams, G. J., Marvin, M., Caffrey, M. (2015). Ternary structure reveals mechanism of a membrane diacylglycerol kinase. Nature communications. Vol. 6, pp. 10140. PubMed Web Address
• Yefanov, O., Mariani, V., Gati, C., White, T. A., Chapman, H. N., Barty, A. (2015). Accurate determination of segmented X-ray detector geometry. Optics express. Vol. 23 (22), pp. 28459-70. PubMed Web Address
• Panneels, V., Wu, W., Tsai, C. J., Nogly, P., Rheinberger, J., Jaeger, K., Cicchetti, G., Gati, C., Kick, L. M., Sala, L., Capitani, G., Milne, C., Padeste, C., Pedrini, B., Li, X. D., Standfuss, J., Abela, R., Schertler, G. (2015). Time-resolved structural studies with serial crystallography: A new light on retinal proteins. Structural dynamics (Melville, N.Y.). Vol. 2 (4), pp. 041718. PubMed Web Address
• Kang, Y., Zhou, X. E., Gao, X., He, Y., Liu, W., Ishchenko, A., Barty, A., White, T. A., Yefanov, O., Han, G. W., Xu, Q., de, P. W., Ke, J., Tan, M. H., Zhang, C., Moeller, A., West, G. M., Pascal, B. D., Van, N., Caro, L. N., Vishnivetskiy, S. A., Lee, R. J., Suino-Powell, K. M., Gu, X., Pal, K., Ma, J., Zhi, X., Boutet, S., Williams, G. J., Messerschmidt, M., Gati, C., Zatsepin, N. A., Wang, D., James, D., Basu, S., Roy-Chowdhury, S., Conrad, C. E., Coe, J., Liu, H., Lisova, S., Kupitz, C., Grotjohann, I., Fromme, R., Jiang, Y., Tan, M., Yang, H., Li, J., Wang, M., Zheng, Z., Li, D., Howe, N., Zhao, Y., Standfuss, J., Diederichs, K., Dong, Y., Potter, C. S., Carragher, B., Caffrey, M., Jiang, H., Chapman, H. N., Spence, J. C., Fromme, P., Weierstall, U., Ernst, O. P., Katritch, V., Gurevich, V. V., Griffin, P. R., Hubbell, W. L., Stevens, R. C., Cherezov, V., Melcher, K., Xu, H. E. (2015). Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature. Vol. 523 (7562), pp. 561-7. PubMed Web Address
• Conrad, C. E., Basu, S., James, D., Wang, D., Schaffer, A., Roy-Chowdhury, S., Zatsepin, N. A., Aquila, A., Coe, J., Gati, C., Hunter, M. S., Koglin, J. E., Kupitz, C., Nelson, G., Subramanian, G., White, T. A., Zhao, Y., Zook, J., Boutet, S., Cherezov, V., Spence, J. C., Fromme, R., Weierstall, U., Fromme, P. (2015). A novel inert crystal delivery medium for serial femtosecond crystallography. IUCrJ. Vol. 2 (Pt 4), pp. 421-30. PubMed Web Address
• Wu, W., Nogly, P., Rheinberger, J., Kick, L. M., Gati, C., Nelson, G., Deupi, X., Standfuss, J., Schertler, G., Panneels, V. (2015). Batch crystallization of rhodopsin for structural dynamics using an X-ray free-electron laser. Acta crystallographica. Section F, Structural biology communications. Vol. 71 (Pt 7), pp. 856-60. PubMed Web Address
• Barends, T., White, T. A., Barty, A., Foucar, L., Messerschmidt, M., Alonso-Mori, R., Botha, S., Chapman, H., Doak, R. B., Galli, L., Gati, C., Gutmann, M., Koglin, J., Markvardsen, A., Nass, K., Oberthur, D., Shoeman, R. L., Schlichting, I., Boutet, S. (2015). Effects of self-seeding and crystal post-selection on the quality of Monte Carlo-integrated SFX data. Journal of synchrotron radiation. Vol. 22 (3), pp. 644-52. PubMed Web Address
• Zhang, H., Unal, H., Gati, C., Han, G. W., Liu, W., Zatsepin, N. A., James, D., Wang, D., Nelson, G., Weierstall, U., Sawaya, M. R., Xu, Q., Messerschmidt, M., Williams, G. J., Boutet, S., Yefanov, O. M., White, T. A., Wang, C., Ishchenko, A., Tirupula, K. C., Desnoyer, R., Coe, J., Conrad, C. E., Fromme, P., Stevens, R. C., Katritch, V., Karnik, S. S., Cherezov, V. (2015). Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell. Vol. 161 (4), pp. 833-44. PubMed Web Address
• Fenalti, G., Zatsepin, N. A., Betti, C., Giguere, P., Han, G. W., Ishchenko, A., Liu, W., Guillemyn, K., Zhang, H., James, D., Wang, D., Weierstall, U., Spence, J. C., Boutet, S., Messerschmidt, M., Williams, G. J., Gati, C., Yefanov, O. M., White, T. A., Oberthuer, D., Metz, M., Yoon, C. H., Barty, A., Chapman, H. N., Basu, S., Coe, J., Conrad, C. E., Fromme, R., Fromme, P., Tourwé, D., Schiller, P. W., Roth, B. L., Ballet, S., Katritch, V., Stevens, R. C., Cherezov, V. (2015). Structural basis for bifunctional peptide recognition at human δ-opioid receptor. Nature structural & molecular biology. Vol. 22 (3), pp. 265-8. PubMed Web Address
• Tenboer, J., Basu, S., Zatsepin, N., Pande, K., Milathianaki, D., Frank, M., Hunter, M., Boutet, S., Williams, G. J., Koglin, J. E., Oberthuer, D., Heymann, M., Kupitz, C., Conrad, C., Coe, J., Roy-Chowdhury, S., Weierstall, U., James, D., Wang, D., Grant, T., Barty, A., Yefanov, O., Scales, J., Gati, C., Seuring, C., Srajer, V., Henning, R., Schwander, P., Fromme, R., Ourmazd, A., Moffat, K., Van, J. J., Spence, J. C., Fromme, P., Chapman, H. N., Schmidt, M. (2014). Time-resolved serial crystallography captures high-resolution intermediates of photoactive yellow protein. Science (New York, N.Y.). Vol. 346 (6214), pp. 1242-6. PubMed Web Address
• Stellato, F., Oberthür, D., Liang, M., Bean, R., Gati, C., Yefanov, O., Barty, A., Burkhardt, A., Fischer, P., Galli, L., Kirian, R. A., Meyer, J., Panneerselvam, S., Yoon, C. H., Chervinskii, F., Speller, E., White, T. A., Betzel, C., Meents, A., Chapman, H. N. (2014). Room-temperature macromolecular serial crystallography using synchrotron radiation. IUCrJ. Vol. 1 (Pt 4), pp. 204-12. PubMed Web Address
• Yefanov, O., Gati, C., Bourenkov, G., Kirian, R. A., White, T. A., Spence, J. C., Chapman, H. N., Barty, A. (2014). Mapping the continuous reciprocal space intensity distribution of X-ray serial crystallography. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. Vol. 369 (1647), pp. 20130333. PubMed Web Address
• Gati, C., Bourenkov, G., Klinge, M., Rehders, D., Stellato, F., Oberthür, D., Yefanov, O., Sommer, B. P., Mogk, S., Duszenko, M., Betzel, C., Schneider, T. R., Chapman, H. N., Redecke, L. (2014). Serial crystallography on in vivo grown microcrystals using synchrotron radiation. IUCrJ. Vol. 1 (Pt 2), pp. 87-94. PubMed Web Address
• Weierstall, U., James, D., Wang, C., White, T. A., Wang, D., Liu, W., Spence, J. C., Bruce, R., Nelson, G., Fromme, P., Fromme, R., Grotjohann, I., Kupitz, C., Zatsepin, N. A., Liu, H., Basu, S., Wacker, D., Han, G. W., Katritch, V., Boutet, S., Messerschmidt, M., Williams, G. J., Koglin, J. E., Marvin, M., Klinker, M., Gati, C., Shoeman, R. L., Barty, A., Chapman, H. N., Kirian, R. A., Beyerlein, K. R., Stevens, R. C., Li, D., Shah, S. T., Howe, N., Caffrey, M., Cherezov, V. (2014). Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography. Nature communications. Vol. 5, pp. 3309. PubMed Web Address
• Liu, W., Wacker, D., Gati, C., Han, G. W., James, D., Wang, D., Nelson, G., Weierstall, U., Katritch, V., Barty, A., Zatsepin, N. A., Li, D., Messerschmidt, M., Boutet, S., Williams, G. J., Koglin, J. E., Seibert, M. M., Wang, C., Shah, S. T., Basu, S., Fromme, R., Kupitz, C., Rendek, K. N., Grotjohann, I., Fromme, P., Kirian, R. A., Beyerlein, K. R., White, T. A., Chapman, H. N., Caffrey, M., Spence, J. C., Stevens, R. C., Cherezov, V. (2013). Serial femtosecond crystallography of G protein-coupled receptors. Science (New York, N.Y.). Vol. 342 (6165), pp. 1521-4. PubMed Web Address
• Demirci, H., Sierra, R. G., Laksmono, H., Shoeman, R. L., Botha, S., Barends, T. R., Nass, K., Schlichting, I., Doak, R. B., Gati, C., Williams, G. J., Boutet, S., Messerschmidt, M., Jogl, G., Dahlberg, A. E., Gregory, S. T., Bogan, M. J. (2013). Serial femtosecond X-ray diffraction of 30S ribosomal subunit microcrystals in liquid suspension at ambient temperature using an X-ray free-electron laser. Acta crystallographica. Section F, Structural biology and crystallization communications. Vol. 69 (Pt 9), pp. 1066-9. PubMed Web Address
• Jarahian, M., Fiedler, M., Cohnen, A., Djandji, D., Hämmerling, G. J., Gati, C., Cerwenka, A., Turner, P. C., Moyer, R. W., Watzl, C., Hengel, H., Momburg, F. (2011). Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS pathogens. Vol. 7 (8), pp. e1002195. PubMed Web Address
• 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 fingerprints of a convergent mechanism orchestrating diverse ligand recognition and species-specific pharmacology at the complement anaphylatoxin receptors. bioRxiv : the preprint server for biology. 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
• Molecular mechanisms of metabotropic GABA(B) receptor function. Science advances. Vol. 7 (22) PubMed Web Address
• Structure of the essential inner membrane lipopolysaccharide-PbgA complex. Nature. Vol. 584 (7821), pp. 479-483. 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
• XFEL structures of the human MT(2) melatonin receptor reveal the basis of subtype selectivity. Nature. Vol. 569 (7755), pp. 289-292. PubMed Web Address
• Crystal structure of misoprostol bound to the labor inducer prostaglandin E(2) receptor. Nature chemical biology. Vol. 15 (1), pp. 11-17. PubMed Web Address
• Serial femtosecond crystallography datasets from G protein-coupled receptors. Scientific data. Vol. 3, pp. 160057. PubMed Web Address
• Femtosecond structural dynamics drives the trans/cis isomerization in photoactive yellow protein. Science (New York, N.Y.). Vol. 352 (6286), pp. 725-9. PubMed Web Address
• Recent developments in CrystFEL.