S. Swaminathan

S. Swaminathan is the principal investigator of the Structural Genomics Intitive at the BNL Biology Department which is a partner in the New York Structural Genomics Research Consortium. The NYSGRC is a collaboratory of the Albert Einstein College of Medicine, BNL, Columbia University, Structural Genomics Inc., The Rockefeller University, University of California at San Francisco, and the Sloan Kettering Institute. The BNL Biology group is advancing the efficient crystallographic structure determination of NYSGRC targeted proteins, and currently includes the following scientists and post doctoral fellows: S. Swaminathan, S. Eswaramoorthy, D. Kumaran, R. Agarwal, S. Jayaraman, N. Krishnamurthy, and J-S. Jiang.

 

 

Research Interests

We are interested in understanding the structure-function relationship in macromolecules, especially bacterial toxins, via x-ray crystallography. Research projects include structural work on Staphylococcus aureus enterotoxins, Clostridium botulinum neurotoxins, Clostridium perfringens enterotoxin, outer surface proteins of Borrelia burgdorferi, Shewanella putrefaciens proteins involved in metal reduction, etc.

Staphylococcal enterotoxins (SE's) are called superantigens because of their ability to induce massive T cell proliferation when they are presented by major histocompatibility complex class II molecules (MHCII). MHCII and SE form a ternary complex with T cell receptors (TCR) and stimulate all T cells bearing particular V-beta elements. This is because the binding is induced by the nature of V-beta chain of TCR only. The structure determination of staphylococcal enterotoxin B (SEB) revealed the binding sites of MHCII and the T cell receptor on SEB. It was also shown that all staphylococcal enterotoxins might possess a common fold called SE-fold. The structure determination of a second serotype, C2, of staphylococcal enterotoxin confirmed these findings. These two structures along with theoretical models of SEA and SEE helped in identifying residues in these enterotoxins that may be responsible for TCR V-beta specificity although they all have a common fold and high sequence homology. We are working on complexes of SEB with small molecules, which inactivate the toxin.

Currently we are working on the structures of Clostridium botulinum neurotoxins (BoNT), which are extremely potent toxins. These are food poisons that are produced by the bacteria after their growth in improperly stored foods that sustain anaerobic conditions. These toxins have attracted worldwide attention since they are being employed as bio-warfare agents. However, they are also approved by FDA for therapeutic purposes. It is gaining importance in clinical use. The crystal structure of Clostridum botulinum neurotoxin B has recently been determined to a high resolution. We are currently studying structures of botulinum neurotoxins with inhibitors, which would lead to the development of drugs for this toxin. A major question in the food-borne botulism is how BoNT is able to resist the digestive system of the gastrointestinal tract (GT). This is because the neurotoxins are released with a group of proteins which form a tight complex. These associated proteins protect them from the low pH and proteases of the GT. Such activities are crucial for the food poisoning activity of neurotoxins. Understanding of this system could provide clues to use of these associated proteins as carriers of oral vaccines. Work on these proteins and their complexes with neurotoxins is in progress.

In addition to the above projects, we are involved in the Structural Genomics project and the Lyme disease project.

The article 'At the NSLS, BNL Biologists Decipher Structure of Botulism-Causing Toxin' gives an account of our recent work. See the Brookhaven Bulletin of Aug. 11, 2000 (Vol 54 No 28). Our contributions to the New York Structural Genomics Research Consortium (NYSGRC) is summarized in the Brookhaven Bulletin of Nov. 3, 2000 (Vol 54 No 39). and an article on OspC 'Lyme Disease Protein Structure Determined at BNL' appeared in the Brookhaven Bulletin of March 2, 2001 (Vol 55 No 6).

The annotated structure gallery gives several recently determined structures. (click on any).

 

Resent News

• Scientists Get Funding to Design Anti-Botulism Drugs

 

Selected Publications

• Sugadev R., Sauder J.M., Burley S.K., and Swaminathan S.
  Structural studies on cytosolic domain of Magnesium transporter MgtE from Enterococcus faecalis.
  Proteins, 2009 (in press)
• Agarwal R., Schmidt J.J., Stafford R.G., and Swaminathan S.
  Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F.
  Nature Structural and Molecular Biology, 16:789-794 (2009).  PubMed
• Kumaran D., Eswaramoorthy S., Furey W., Navaza J., Sax M., and Swaminathan S.
  Domain organization in Clostridium botulinum neurotoxin type E is unique: Its implication in faster translocation.
  Journal of Molecular Biology, 386(1):233-245 (February, 2009).  PubMed
• Pieper U., Chiang R., Seffernick J.J., Brown S.D., Glasner M.E., Kelly L., Eswar N., Sauder J.M., Bonanno J.B., Swaminathan S., Burley S.K., Zheng X., Chance M.R., Almo S.C., Gerlt J.A., Raushel F.M., Jacobson M.P., Babbitt C., and Sali A.
  Target selection and annotation for the structural genomics of the amidohydrolase and enolase superfamilies.
  Journal of Structural Functional Genomics, 10(2):107-125 (April, 2009).  PubMed
• Swaminathan S.
  Molecular structures and functional relationships of botulinum neurotoxins.
  Botulinum and Other Neurotoxins: Translating Science into Therapeutic Applications, J. Jankovic et al., Chapter 2, Elsevier Publisher (in press).
• Xiang, D. F., Xu, C., Kumaran, D., Brown, A. C., Sauder, J. M., Burley, S. K., Swaminathan S., and Raushel, F. M.
  Functional annotation of two new carboxypeptidases from the amidohydrolase superfamily of enzymes.
  Biochemistry, 48(21):4567-4576 (April, 2009).   PubMed
• Agarwal R., Burley S.K. and Swaminathan S.
  Structure of human dual specificity protein phosphatase 23, VHZ, enzyme-substrate/product complex.
  Journal of Biological Chemistry, 283(14): 8946-8953 (2008).    PubMed
• Agarwal R., Burley S.K. and Swaminathan S.
  A novel mode of dimerization via formation of a glutamate anhydride crosslink in a protein crystal structure.
  Proteins, Structure, Function and Bioinformatics 71(2):1038-1041 (2008).    PubMed
• Agarwal R. and Swaminathan S.
  SNAP-25 substrate peptide (residues 180-183) binds to but bypasses cleavage by catalytically active Clostridium botulinum neurotoxin E.
  Journal of Biological Chemistry, 283(38):25944-25951 (2008).  PubMed
• Graslund S., Nordlund P., Weigelt J., Bray J., Gileadi O., Knapp S., Oppermann U., Arrowsmith C., Hui R., Ming J., dhe-Paganon S., Park H.-W., Savchenko A., Yee A., Edwards A., Vincentelli R., Cambillau C., Kim R., Kim S.-H., Rao Z., Shi Y., Terwilliger T.C., Kim C.-Y., Hung L.-W., Waldo G.S., Peleg Y., Albeck S., Unger T., Dym O., Prilusky J., Sussman J.L., Stevens R.C., Lesley S.A., Wilson I.A., Joachimiak A., Collart F., Dementieva I., Donnelly M.I., Eschenfeldt W.H., Kim Y., Stols L., Wu R., Zhou M., Burley S.K., Emtage J.S., Sauder J.M., Thompson D., Bain K., Luz J., Gheyi T., Zhang F., Atwell S., Almo S.C., Bonanno J.B., Fiser A., Swaminathan S., Studier F.W., Chance M.R., Sali A., Acton T.B., Xiao R., Zhao R., Zhao L., Ma L.C., Hunt J.F., Tong L., Cunningham K., Inouye M., Anderson S., Janjua H., Shastry R., Ho C.K., Wang D., Wang H., Jiang M., Montelione G.T., Stuart D.I., Owens R.J., Daenke S., Schutz A., Heinemann U., Yokoyama S., Bussow K., and Gunsalus K.C.
  Protein production and purification.
  Nature Methods, 5(2):135-146 (2008).  PubMed
• Kumaran D., Rawat R., Ahmed S.A. and Swaminathan S.
  Substrate binding mode and its implication on drug design for Botulinum neurotoxin A.
  PLoS Pathogens 4(9): e1000165 (2008).  PubMed
• Kumaran D., Rawat R., Ludivico M.L., Ahmed S.A. and Swaminathan S.
  Structure and substrate based inhibitor design for Clostridium botulinum neurotoxin serotype A.
  Journal of Biological Chemistry 283(27):18883-18891 (2008).  PubMed
• Legler P.M., Kumaran D., Swaminathan S., Studier F.W. and Millard C.B.
  Structural characterization and reversal of the natural organophosphate resistance of a D-type esterase, Saccharomyces cerevisiae S-formylglutathione hydrolase.
  Biochemistry, 47(36):9592-9601 (2008).  PubMed
• Madegowda M., Eswaramoorthy S., Burley S.K. and Swaminathan S.
  X-ray crystal structure of the B component of Hemolysin BL from Bacillus cereus.
  PROTEINS: Structure, Function, and Bioinformatics, 71(2):534-540 (2008).  PubMed
• Mazumdar P.A., Kumaran D., Swaminathan S. and Das A.K.
  A novel acetate-bound complex of human carbonic anhydrase II.
  Acta Crystallographica Section F: Structural Biology and Crystallization Communications F64 (Pt. 3):163-166 (2008).  PubMed
• Ragumani S., Kumaran D., Burley S.K. and Swaminathan S.
  Crystal structure of a putative lysostaphin peptidase from Vibrio cholerae.
  PROTEINS: Structure, Function, and Bioinformatics, 72(3):1096-1103 (2008).  PubMed
• Rao K.N., Burley S.K., and Swaminathan S.
  UPF201 archaeal specific family members reveal structural similarity to RNA-binding proteins but low likelihood of RNA-binding function.
  PLoS One, 3(12):e3903-1 to -12 (December, 2008).
• Rawat R., Ahmed S.A. and Swaminathan S.
  High level expression of the light chain of Botulinum neurotoxin serotype C1 and an efficient HPLC assay to monitor its proteolytic activity.
  Protein Expression and Purification, 60(2):165-169 (2008).  PubMed
• Swaminathan S.
  Molecular structures and functional relationships of botulinum neurotoxins. Botulinum and Other Neurotoxins: Translating Science into Therapeutic Applications, J. Jankovic et al., Editors, Elsevier Publishers Chapter 2, Elsevier Publisher (in press).
• Tyagi R., Eswaramoorthy S., Burley S.K., Raushel F.M. and Swaminathan S.
  A common catalytic mechanism for proteins of HutI family.
  Biochemistry 47(20): 5608-5615 (2008).  PubMed
• Agarwal R., Burley S.K., and Swaminathan S.
  Structural analysis of a ternary complex of allantoate amidohydrolase from Escherichia coli reveals its mechanics.
  J. Mol. Biol. 368(2): 450-463 (2007).   PubMed
• Almo S.C., Bonanno J.B., Sauder J.M., Emtage S., Dilorenzo T.P., Malashkevich V., Wasserman S.R., Swaminathan S., Eswaramoorthy S., Agarwal R., Kumaran D., Madegowda M., Ragumani S., Patskovsky Y., Alvarado J., Ramagopal U.A., Faber-Barata J., Chance M.R., Sali A., Fiser A., Zhang Z.Y., Lawrence D.S. and Burley S.K.
  Structural genomics of protein phosphatases.
  J. Struct. Funct. Genomics 8(2-3): 121-140 (2007).   PubMed
• Rao K.N., Burley S.K. and Swaminathan S.
  Crystal structure of a conserved protein of unknown function (MJ1651) from Methanococcus jannaschii.
  PROTEINS: Structure, Function, and Bioinformatics 70(2): 572-577 (2007).   PubMed
• Tyagi R., Burley S.K. and Swaminathan S.
  X-ray structures of two proteins belonging to Pfam DUF178 revealed unexpected structural similarity to the DUF191 Pfam family.
  BMC Struct Biol. 7:62 (2007). PubMed
• Tyagi R., Kumaran D., Burley S.K. and Swaminathan S.
  X-ray structure of imidazolonepropionase from Agrobacterium tumefaciens at 1.87 Å resolution.
  PROTEINS: Structure, Function, and Bioinformatics 69(3): 652-658 (2007).   PubMed
• Agarwal R., Bonanno J.B., Burley S.K. and Swaminathan S.
  Structure determination of an FMN reductase from Pseudomonas aeruginosa PA01 using sulfur anomalous signal.
  Acta Cryst. D62(Pt.4): 383-391 (2006).   PubMed
• Eswaramoorthy S., Bonanno J.B., Burley S.K. and Swaminathan S.
  Mechanism of action of a flavin-containing monooxygenase.
  Proc. Natl. Acad. Sci. USA 103(26): 9832-9837 (2006).   PubMed
• Rao K.N., Bonanno J.B., Burley S.K. and Swaminathan S.
  Crystal structure of glycerophosphodiester phosphodiesterase from Agrobacterium tumefaciens by SAD with a large asymmetric unit.
  PROTEINS: Structure, Function, and Bioinformatics 65(2): 514-518 (2006).   PubMed
  Cover: Ribbon representation of trehalose-6-phosphate phosphatase with its hydrolase and cap domains in blue and red. Magnesium ion (Mg, in magenta) required for catalytic activity and the coordinating residues (in yellow) are shown in ball-and-stick model. A sodium ion and glycerol molecules present in the crystal structure are also shown. The glycerol molecule at the active site occupies the trehalose-6-phosphate binding site.
• Rao K.N., Kumaran D., Seetharaman J., Bonanno J.B., Burley S.K. and Swaminathan S.
  Crystal structure of trehalose-6-phosphate phosphatase-related protein: Biochemical and biological implications.
  Protein Science 15(7): 1735-1744 (2006).   PubMed
• Seetharaman J., Kumaran D., Bonanno J.B., Burley S.K. and Swaminathan S.
  Crystal structure of a putative HTH-type transcriptional regulator yxaF from Bacillus subtilis.
  PROTEINS: Structure, Function, and Bioinformatics 63(4): 1087-1091 (2006).   PubMed
• Seetharaman J., Rajashankar K.R., Solorzano V., Kniewel R., Lima C.D., Bonanno J.B., Burley S.K. and Swaminathan S.
  Crystal structures of two putative phosphoheptose isomerases.
  PROTEINS: Structure, Function, and Bioinformatics 63(4): 1092-1096 (2006).   PubMed
• Sikorra S., Henke T., Swaminathan S., Galli T. and Binz T.
  Identification of the amino acid residues rendering TI-VAMP insensitive toward Botulinum neurotoxin B.
  J. Mol. Biol. 357(2): 574-582 (2006).   PubMed
• Agarwal R., Binz T. and Swaminathan S.
  Analysis of active site residues of botulinum neurotoxin E by mutational, functional and structural studies: Glu335Gln is an apoenzyme.
  Biochemistry 44(23): 8291-8302 (2005).   PubMed
• Agarwal R., Binz T. and Swaminathan S.
  Structural analysis of botulinum neurotoxin serotype F light chain: Implications on substrate binding and inhibitor design.
  Biochemistry 44(35): 11758-11765 (2005).   PubMed
• Bonanno J.B., Almo S.C., Bresnick A., Chance M.R., Fiser A., Swaminathan S., Jiang J., Studier F.W., Shapiro L., Lima C.D., Gaasterland T.M., Sali A., Bain K., Feil I., Gao X., Lorimer D., Ramos A., Sauder J.M., Wasserman S.R., Emtage S., D’Amico K.L. and Burley S.K.
  New York-Structural GenomiX Research Consortium (NYSGXRC): A large scale center for the protein structure initiative.
  J. Struct. Funct. Genomics 6(2-3): 225-232 (2005).   PubMed
• Jayaraman S., Eswaramoorthy S., Ahmed S.A., Smith L.A. and Swaminathan S.
  N-terminal helix reorients in recombinant C-fragment of Clostridium botulinum type B.
  Biochemical Biophysical Research Communication 330(1): 97-103 (2005).   PubMed
• Jayaraman S., Eswaramoorthy S., Kumaran D. and Swaminathan S.
  Common binding site for disialyllactose and tri-peptide in C-fragment of tetanus neurotoxin.
  PROTEINS: Structure, Function, and Bioinformatics 61(2): 288-295 (2005).   PubMed
• Kumaran D., Eswaramoorthy S., Studier F.W. and Swaminathan S.
  Structure and mechanism of ADP-ribose-1”-monophosphatase (Appr-1”-pase), a ubiquitous cellular processing enzyme.
  Protein Science 14(3): 719-726 (2005).   PubMed
  Cover: Interactions between Appr-1”-pase and its catalytic product ADP-ribose in the product-bound state. Bonds of protein residues are shown in cyan; ADP-ribose and ethylene glycol are shown in gray. Carbon, Oxygen, Nitrogen, and phosphorus atoms are shown in green, red, blue, and purple, respectively. The purple dashed lines indicate the hydrogen bonding.
• Rao K.N., Kumaran D., Binz T. and Swaminathan S.
  Structural analysis of the catalytic domain of tetanus neurotoxin.
  Toxicon 45(7): 929-939 (2005).   PubMed
• Agarwal R., Eswaramoorthy S., Kumaran D., Dunn J.J. and Swaminathan S.
  Cloning high level expression, purification, and crystallization of the full length Clostridium botulinum type E light chain.
  Protein Expression and Purification 34(1): 95-102 (2004).   PubMed
• Eswaramoorthy S., Kumaran D., Keller J. and Swaminathan S.
  Role of metals in the biological activity of Clostridium botulinum neurotoxins.
  Biochemistry 43(8): 2209-2216 (2004).   PubMed
• Swaminathan S.
  Toward therapeutics for Clostridium botulinum neurotoxins.
  Synchrotron Radiation News 17(4):16-24 (2004).  
• Swaminathan S., Eswaramoorthy S. and Kumaran D.
  Structure and enzymatic activity of botulinum neurotoxins.
  Movement Disorders 19(S8): S17-S22 (2004).  

• Agarwal R., Eswaramoorthy S., Kumaran D., Binz T. and Swaminathan S.
  Structural analysis of botulinum neurotoxin type E catalytic domain and its mutant Glu212Gln reveals the pivotal role of the Glu212 carboxylate in the catalytic pathway.
  Biochemistry 43: 6637-6644 (2004).
  PDB files: 1T3A, 1T3C  Jmol viewer
  For a summary read the BNL Press Release of May 10, 2004.
   

• Yuan P., Jedd G., Kumaran D., Swaminathan S., Shio H., Hewitt D., Chua N.-H., and Swaminathan S.
  A HEX-1 crystal lattice required for Woronin body function in Neurospora crassa.
  Nature Struct. Biol. 10(4): 264-270 (2003).   PubMed   PDB file1KHI

• Kumaran D., Eswaramoorthy S., Gerchman S.E., Kycia H., Studier F.W., Swaminathan S.
  Crystal structure of a putative CN hydrolase from yeast.
  Proteins 52(2): 283-91 (2003).   PubMed   PDB file 1F89

• Eswaramoorthy S., Gerchman S., Graziano V., Kycia H., Studier F.W. and Swaminathan S.
  Structure of a yeast hypothetical protein selected by a structural genomics approach.
  Acta Cryst. D59(1): 127-35 (2003).   PubMed   PDB files 1B54, 1CT5  Jmol viewer

• Eswaramoorthy S., Kumaran D. and Swaminathan S.
  A novel mechanism for Clostridium botulinum neurotoxin inhibition.
  Biochemistry 41(31): 9795-802 (2002).   PubMed   PDB files 1G9A, 1G9B, 1G9C, 1G9D  Jmol viewer
  
• Swaminathan S. and Eswaramoorthy S.
  Crystal structure of Clostridium botulinum neurotoxin serotype B.
  in: Scientific and Therapeutic Aspects of Botulinum Toxin, ( M.F. Brin, M. Hallett, and J. Jankovic, editors) Lippincott Williams & Wilkins, Philadelphia, PA. Chapter 3, pp. 29-39, (2002).

• Eswaramoorthy S., Kumaran D. and Swaminathan S.
  Crystallographic evidence for doxorubicin binding to the receptor-binding site in Clostridium botulinum neurotoxin B.
  Acta Cryst. D57(11): 1743-6 (2001).   PubMed   PDB file 1I1E

• Kumaran D., Eswaramoorthy S., Furey W., Sax M. and Swaminathan S.
  Structure of staphylococcal enterotoxin C2 at various pH levels.
  Acta Cryst. D57(9): 1270-5 (2001).   PubMed   PDB files 1CQV, 1I4P, 1I4Q, 1I4R, 1I4X  Jmol viewer

• Kumaran D., Eswaramoorthy S., Luft B.J., Koide S., Dunn J.J., Lawson C.L. and Swaminathan S.
  Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete, Borrelia burgdorferi.
  EMBO J. 20(5): 971-8 (2001).   PubMed   Full Text (pdf)    PDB files 1F1M, 1GGQ  Jmol viewer

• Swaminathan S. and Eswaramoorthy S.
  Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B.
  Nature Struct. Biol. 7: 693-699 (2000).   PubMed    PDB files 1EPW, 1F31 Jmol viewer
  
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  Burley S.K., Almo S.C., Bonanno J.B., Capel M., Chance M.R., Gaasterland T., Lin D., Sali A., Studier F.W. and Swaminathan S.
  Structural genomics: beyond the human genome project.
  Nat. Genet. 23: 151-157 (1999). PubMed
  

• Umland T.C., Wingert L.M., Swaminathan S., Furey W.F., Schmidt J.J., Sax M.,
  Structure of the receptor binding fragment HC of tetanus neurotoxin.
  Nature Struct. Biol. 4: 788-792 (1997).   PubMed   PDB file 1AF9
• Swaminathan S., Furey W.F. and Sax M.,
  Structure of staphylococcal enterotoxins.
  in: Protein Toxin Structures, M.W. Parker, edt., R.D. Landes Co., Austin TX, pp. 237-251 (1996).
   

• Arjunan P., Umland T., Dyda F., Swaminathan S., Furey W., Sax M., Farrenkopf B., Gao Y., Zhang D. and Jordan F.
  Crystal structure of the thiamin diphosphate-dependent enzyme pyruvate decarboxylase from the yeast Saccharomyces cerevisiae at 2.3 Å resolution.
  J. Mol. Biol. 256: 590-600 (1996).   PubMed   PDB file 1PVD

• Swaminathan S., Furey W., Pletcher J. and Sax M.
  Residues defining V beta specificity in staphylococcal enterotoxins.
  Nature Struct. Biol. 2: 680-686 (1995) .   PubMed   PDB files 1SE2, 1SE3, 1SE4

• Umland T.C., Swaminathan S., Sigh G., Furey W., Pletcher J. and Sax M.
  Structure of a human Clara cell phospholipid-binding protein-ligand complex at 1.9 Å resolution.
  Nature Struct. Biol. 1:538-545 (1994).   PubMed    PDB file 1CCD

• Dyda F., Furey W., Swaminathan S., Sax M., Farrenkopf B. and Jordan F.
  Catalytic centers in the thiamin diphosphate dependent enzyme pyruvate decarboxylase at 2.4-Å resolution.
  Biochemistry 32: 6165-6170 (1993).   PubMed   PDB file 1PYD

• Swaminathan S., Furey W., Pletcher J. and Sax M.
  Crystal structure of staphylococcal enterotoxin B, a superantigen.
  Nature 359: 801-806 (1992).   PubMed   PDB file 1SE2