Structural Biology Laboratory
Professor Senyon Choe joined the Salk Institute in 1993 as the first member of the Institute's newly initiated Structural Biology Laboratory. Choe uses X-ray crystallography as a major tool to determine three-dimensional structures of biologically important molecules. He and his colleagues also study the relationship between a molecule's fine structure and the functions it carries out.
Among Choe's recent interests is the study of molecules that bind to specific cells to instruct them to carry out functions. An extension of this work will explore the possibility of designing new molecules that can be delivered specifically to modulate sick cells. His group also has done pioneering work on the molecular structure of an ion channel, important to many physiological functions ranging from heart rate to nerve cell communication.
"Biological messages are written and delivered between cells by messenger molecules in the body. The two messenger systems we are focusing on are called ion channels (for e-mails) and protein hormone receptors (for snail mail). By visualizing these messengers to better understand how such messages are coded for specific delivery, we can create brand-new messages of our own."
The premise that "form follows function" became a mantra for numerous leading architects and industrial designers during a good part of the last century. In biology, evolution operates according to a similar premise because forms with better functionality are likelier to be selected. Trying to understand the relationship between a molecule's fine structure and the functions it carries out, Choe and his colleagues use x-ray crystallography and NMR spectroscopy to zoom in on ion channels and receptors in the cell membrane to visualize how they interact with messenger proteins. Recent work focused on analyzing the three-dimensional structure of a whole protein complex to illustrate how TGF-beta, a messenger molecule that plays a role in cancer, the immune system and heart disease, binds to its receptor molecules on specific target cells to instruct them to do its bidding. An extension of this work explores the possibility of designing new messages to instruct cells to carry out non-natural processes such as coaxing differentiated cells back into an immature, pluripotent state. These types of newly created messages will have tremendous clinical potential as guiding molecules.
Human integral membrane proteins (hIMPs) are attached to the membrane surrounding each cell, serving as gateways for absorbing nutrients, hormones and drugs; removing waste products; and allowing cells to communicate with their environment. Many diseases, including Alzheimer's, heart disease and cancer, have been linked to malfunctioning hIMPs, and many drugs, ranging from aspirin to schizophrenia medications, target these proteins. These receptors and ion channels are extremely hard to produce and hence notoriously difficult to study, but Choe's group recently developed a new technique for rapidly determining their structure. Knowing the exact three-dimensional shape of hIMPs allows drug developers to understand the precise biochemical mechanisms by which current drugs work and to develop new drugs that target the proteins.
Left to right:
Joseph Peng, Ellis Chiu, Luis Esquivies, Witold Kwiatkowski, Senyon Choe, Innokentiy Maslennikov, Polina Brodsky, Christian Klammt, Matt Lundberg
Choe, S., Bennett, M., Fujii, G., Curmi, P.A.M., Kantardjieff, K.A., Collier, R.J., Eisenberg, D. (1992) Three domains for three functions: The crystal structure of diphtheria toxin. Nature 357, 216-222.
Lovejoy, B., Choe, S., Cascio, D., McRorie, D.K., DeGrado, W.F., Eisenberg, D. (1993) Crystal structure of a synthetic triple-stranded alpha-helical bundle. Science 259, 1288-1293.
Bennett, M., Choe, S., Eisenberg, D. (1994) Domain Swapping: Proteins in entangled alliances, Proc. Natl. Acad. Sci. 91, 3127-3131.
Choe, S., Stevens, C.F., Sullivan, J.M. (1995) Three distinct structural environments of a transmembrane domain of the inwardly rectifying potassium channel defined by perturbation. Proc. Natl. Acad. Sci. USA 92, 12046-12049.
Louie, G., Yang, W., Bowman, M., Choe, S. (1997) Crystal structure of diphtheria toxin in complex with an extracellular fragment of its receptor, Molecular Cell 1, 67-78.
Kreusch, A., Pfaffinger, P., Stevens, C.F., Choe, S. (1998) Crystal structure of the tetramerization domain of the Shaker potassium channel. Nature 392, 945-8.
Choe, S., Robinson, R. (1998) An ingenious filter: the structural basis of ion selectivity. Neuron 20, 821-3.
Ryan, A., Blumberg, B., Rodriguez-Estaban, C., Yonie-Tamura, S., Tamura, K., Tsukui, T., Peña, J., Sabbagh, W., Greenwald, J., Choe, S., Norris, D.P., Robertson, E.J., Evans, R.M., Rosenfeld, M.G., Belmonte, J. (1998) Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 394, 545-51.
Greenwald, J., Fischer, W., Vale, W.W., Choe, S. (1999) Three finger toxin fold for the extracellular ligand-binding domain of type II activin receptor kinase. Nature Struc. Biol. 6, 18-22.
Bixby, K., Nanao, M., Shen, V., Kreusch, A., Bellamy, H., Pfaffinger, P., Choe, S. (1999) Zn2+-mediated and molecular determinants of tetramerization in voltage-gated K+ channels. Nature Struc. Biol., 6, 38-43.
Robinson, R., Mejilano, M., Le, V., Burtnick, L.D., Yin, H.L., Choe, S. (1999) Domain movement in gelsolin: a Ca-activated switch. Science, 286, 1939-1942.
Cushman, S.J., Nanao, M.H., Jahng, A.W., DeRubeis, D., Choe, S., Pfaffinger, P.J. (2000) Voltage-dependent activation of potassium channels is coupled to T1 domain structure. Nature Struc. Biol., 7, 403-407.
Robinson, R., Choe, S., Burtnick, L.D. (2001) Disintegration of actin filaments: a role of gelsolin. Proc. Natl. Acad. Sci., 98, 2117-2118.
Zhou, W., Arrabit, C., Choe, S., Slesinger, P. (2001) Bupivacaine inhibits ethanol- and G protein-gated inwardly rectifying K channels. Proc. N. A. S., 98, 6482-7.
Robinson, R., Turbedsky, K., Kaiser, D., Higgs, H.N., Marchand, J., Choe, S., Pollard, T.D. (2001) Crystal structure of Arp2/3 complex. Science, 294, 1679-84.
Choe, S. (2002) Potassium Channel Structures. Nature Reviews Neurosci., 3, 115-121.
Roosild, T., Miller, S., Booth, I., Choe, S. (2002) A mechanism of regulation for potassium flux mediated by conformational change. Cell, 109, 781-791.
Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A., Kwaitkowski, W., Affolter, M., Vale, W., I.-Belmonte, J.-C., Choe, S. (2002) Structural basis of BMP signaling inhibition by Noggin, a novel cystine knot protein. Nature, 420, 636-642.
Greenwald, J., Groppe, J., Gray, P., Wiater, E., Kwiatkowski, W., Vale, W., Choe, S.. (2003) The BMP7/ActRII extracellular domain complex provides new insights into the cooperative nature of receptor assembly. Molecular Cell, 11, 605-17.
Zhou, W., Qian, Y., Kunjilwar, K., Pfaffinger, P.J., Choe, S. (2004) Structural Insights into the Functional Interaction of KChIP1 with Shal-Type K+ Channels. Neuron 41, 573-586.
Greenwald, J., Vega, M., Allendorph, G., Fischer, W., Vale, W., Choe, S. (2004) A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors. Molecular Cell, 15, 485-9
Roosild, T.P., Greenwald, J., Vega, M., Castronovo, S., Riek, R., and Choe, S. (2005) NMR Structure of Mistic, a Membrane-Integrating Protein for Membrane Protein Expression Science 307,1317-21.
Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P., Choe, S. (2005) Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature Neuroscience. 8, 279-287.
Allendorph, G., Vale, W.W., Choe, S. (2006) Structure of the ternary signaling complex of a TGF-b superfamily member. Proc. Natl. Acad. Sci., 103, 7643-8.
Kuo, M. M-C., Baker, K.A., Wong, L., Choe, S. (2007) Dynamic oligomeric conversions of the cytoplasmic RCK domains mediate MthK potassium channel activity. Proc. Natl. Acad. Sci. 104, 2151-6.
Maslennikov, I., Klammt, C., Hwang, E., Kefala, G., Okamura, M., Esquivies, L., Mors, K., Glaubitz, C., Kwiatkowski, W., Jeon Y.H., Choe, S. (2010) Membrane domain structures of three classes of histidine kinase receptors by cell-free expression and rapid NMR analysis. Proc. Natl. Acad. Sci. USA, 107, 10902-7.
Allendorph, G., Read, J.D., Kawakami, Y., Kelber, J.A., Isaacs, M.J., Choe, S. (2011) Designer TGF-beta superfamily ligands with diversified functionality. PLoS One, 6, e26402.
Farina, A.N., Blain, K.Y., Maruo, T., Kwiatkowski, W., Choe, S., Nakagawa, T. (2011) Separation of domain contacts is required for heterotetrameric assembly of functional NMDA receptors. J. Neurosci. 31: 3565-79.
Balana, B., Maslennikov, I., Kwiatkowski, W., Stern, K.M., Bahima, L., Choe, S., Slesinger, P.A. (2011) Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27. Proc. Natl. Acad. Sci. 108: 5831-6.
Klammt, C., Maslennikov, I., Bayrhuber, M., Eichmann, C., Vajpai, N., Chiu, E.J.C., Blain, K., Esquivies, L., Kwon, J.H.J., Balana, B., Pieper, U., Sali, A., Slesinger, P., Kwiatkowski, W., Riek, R., Choe, S. (2012) Facile NMR structure determination of human membrane proteins. Nature Methods, 9, 834-9.
Ou, H.D., Kwiatkowski, W., Deerinck, T., Noske, A., Blain, K.Y., Land, H., Soria, C., Powers, C.J., Shu, X., Tsien, R., Fitzpatrick, J.A.J., Long, J.A., Ellisman, M.H., Choe,S., O'Shea, C.C. (2012) Structure of E4-ORF3 reveals a viral supramolecular assembly that inactivates multiple tumor suppressors. Cell, 151, 304-19.
Salk News Releases
Speeding up drug discovery with rapid 3D mapping of proteins
May 29, 2012
Salk scientists crack molecular code regulating neuronal excitability
March 21, 2011
Site for alcohol's action in the brain discovered
June 28, 2009
Elastic Gateway in Ion Channel Discovered
March 24, 2005
'Mistic' Breakthrough in Membrane Science
February 24, 2005
Structure of Molecular Scissors Critical for the Shaping of Cells Revealed by Structural Biologists at The Salk Institute
December 2, 1999
Zinc Found To Be Integral Part Of Brain Communication Channels
January 6, 1999
Awards and Honors
- Klingenstein Fellowship Award in Neurosciences, 1997
- AAAS Fellow, 1999