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So Iwata is David Blow Chair of Biophysics, Imperial College, London, Diamond Fellow, Diamond Light Source and BBSRC Diamond Professorial Fellow
Membrane proteins are the supreme example where more effort is needed in structural biology. In spite of their abundance and importance, of the more than 50,000 protein structures in the Protein Data Bank, only some 200 of these structures represent unique membrane proteins. Many major questions remain unanswered; these include the signal transduction mechanism of receptors, the gating mechanisms of ion channels and the molecular transport mechanism of transporters. Our group is developing techniques to solve the bottlenecks in membrane protein crystallography. We are currently focusing on the structural studies on the mammalian receptors and transporters, which are the membrane proteins with medical or pharmacological relevance and are the measure drug targets. For the studies, we are liaising with the Diamond-Membrane Protein Laboratory (Diamond-MPL), a laboratory for high throughput protein crystallization/crystallography of difficult targets including membrane proteins and protein complexes.
Towards the molecular mechanism of solute carrier proteins: The results of various genome projects have shown that up to 30% of human proteins occur in cell membranes. The membrane transporters form the second largest family among these membrane proteins and play crucial roles in many biological functions. Although a large amount of work has been done in biochemistry and molecular biology, very little is known about the molecular details and mechanisms of these transporters. The current classification of transporters and proposed molecular mechanisms could be totally re-written once a variety of transporter structures are solved. Our BBSRC funded research program focuses on structure determination of mammalian solute carriers and their orthologues including facilitative GLUT transporter family (SLC2), the bicarbonate transporter family (SLC4), the sodium/proton exchanger family (SLC9), the sodium bile salt cotransport family (SLC10) and the proton oligopeptide cotransporter family (SLC15). We will combine structural biology, molecular biology and computer simulations to understand their molecular transport mechanisms. To achieve these objectives, new laboratory for transporter purification and characterisation will be set up in RCaH.
Sugawara T, Ito K, Shiroishi M, Tokuda N, Asada H, Yurugi-Kobayashi T, Shimamura T, Misaka T, Nomura N, Murata T, Abe K, Iwata S, Kobayashi T. (2009) "Fluorescence-based optimization of human bitter taste receptor expression in Saccharomyces cerevisiae." Biochem. Biophys. Res. Commun. 382: 704 - 710
Andréll J, Hicks M, Palmer T, Carpenter E, Iwata S, Maher M. (2009) "Crystal Structure of the Acid Induced Arginine Decarboxylase from Escherichia coli: Reversible Decamer Assembly Controls Enzyme Activity." Biochemistry. 48: 3915 - 3927
Yurugi-Kobayashi T, Asada H, Shiroishi M, Shimamura T, Funamoto S, Katsuta N, Ito K, Sugawara T, Tokuda N, Tsujimoto H, Murata T, Nomura N, Haga K, Haga T, Iwata S, Kobayashi T. (2009) "Comparison of functional non-glycosylated GPCRs expression in Pichia pastoris." Biochem. Biophys. Res. Commun. 380(2): 271-6.
Newstead, S., Hobbs, Jordan, D. Carpenter, E.P., Iwata, S. (2008) "Insights into outer membrane protein crystallisation." Mol. Memb. Biol. 25: 631 - 638
Drew, D., Klepsch, M.M., Newstead, S., Faig, R., de Gier, J.-W., Iwata, S., Beis, K. (2008) "The structure of the efflux pump AcrB in complex with bile acid" Mol. Memb. Biol. 25: 677-682
Shimamura, T, Yajima, S, Suzuki, S, Rutherford, NG, O'Reilly, J, Henderson, PJF, Iwata, S. (2008) "Crystallization of the hydantoin transporter Mhp1 from Microbacterium liquefaciens." Acta. Crystallogr. F. 64: 1172-1174
Jormakka, M., Yokoyama, K., Yano, T., Tamakoshi, M., Akimoto, S., Shimamura, T., Curmi, P., Iwata, S., A.D. (2008) "Molecular mechanism of energy conservation in polysulfide respiration." Nat. Struct. Mol. Biol. 15: 730-737.
Weyand, S., Shimamura, T., Yajima, S., Suzuki, S., Mirza O., Krusong, K., Carpenter, E.P., Rutherford, N.G., Hadden, J.M., O'Reilly, J., Ma, P., Saidijam, M., Patching, S.G., Hope, R.J., Norbertczak, H.T., Roach, P.C.J., Iwata, S., Henderson, P.J. F. and Cameron, A.D. (2008) "Molecular basis of the alternating access model of membrane transport: structure of a nucleobase-cation-symport-1 family transporter." Science 322:709-713.
Murata, T., Yamato, I., Kakinuma, Y., Shirouzu, M., Walker, J.E., Yokoyama, S., Iwata, S. (2008) "Ion binding and selectivity of the rotor ring of the Na+-transporting V-ATPase." Proc. Natl. Acad. Sci. U.S.A. 105: 8607-8612.
Yamamoto, M., Unzai, S., Saijo, S., Ito, K., Mizutani, K., Suno-Ikeda, C., Yabuki-Miyata, Y., Terada, T., Toyama, M., Shirouzu, M., Kobayashi, T., Kakinuma, Y., Yamato, I., Yokoyama, S., Iwata, S., Murata, T. (2008) "Interaction and stoichiometry of the peripheral stalk subunits NtpE and NtpF and the N-terminal hydrophilic domain of NtpI of Enterococcus hirae V-ATPase." J. Biol. Chem. 283: 19422-19431.
Newstead, S., Ferrandon, S., Iwata, S. (2008) "Rationalizing alpha-helical membrane protein crystallization." Protein Sci. 17: 466-472.
Drew, D., Newstead, S., Sonoda, Y., Kim, H., von Heijne, G., Iwata, S. (2008)
"GFP-based optimization scheme for the overexpression and purification of eukaryotic membrane proteins in Saccharomyces cerevisiae" Nat. Protoc. 3: 784-798.
Kouwen, TRHM., Andrell, J., Schrijver, R., Dubois, JYF., Maher, MJ., Iwata, S., Carpenter, EP., van Dijl, JM., A.D. (2008) "Thioredoxin A active-site mutants form mixed disulfide dimers that resemble enzyme-substrate reaction intermediates." J. Mol. Biol. 379: 520-534.
Ito, K., Sugawara, T., Shiroishi, M., Tokuda, N., Kurokawa, A., Misaka, T., Makyio, H., Yurugi-Kobayashi, T., Shimamura, T., Nomura, N., Murata, T., Abe, K., Iwata, S., Kobayashi, T., A.D. (2008) "Advanced method for high-throughput expression of mutated eukaryotic membrane proteins in Saccharomyces cerevisiae."
Biochem. Bioph. Res. Co. 371: 841-845.
Carpenter, E.P., Beis, K., Cameron, A.D., Iwata, S. (2008) "Overcoming the challenges of membrane protein crystallography." Curr. Opin. Struct. Biol. 18(5):581-586.
Newstead, S., Kim, H., von Heijne, G., Iwata, S., Drew, D. (2007)
"High-throughput fluorescent-based optimization of eukaryotic membrane protein overexpression and purification in Saccharomyces cerevisiae." Proc. Natl. Acad. Sci. USA. 104: 13936-13941.
Guan, L., Mirza, O., Verner, G., Iwata, S., Kaback, HR. (2007)"Structural determination of wild-type lactose permease" P. Natl. Acad. Sci. USA. 104: 15294-15298.
Tanabe, M., Mirza, O., Bertrand, T., Atkins, HS., Titball, RW., Iwata, S., Brown, KA., Byrne, B. (2007) "Structures of OppA and PstS from Yersinia pestis indicate variability of interactions with transmembrane domains." Acta. Crystallogr. D. Biol. Crystallogr. 63; 1185-1193.