Protein & Cell

, Volume 1, Issue 5, pp 435–442 | Cite as

Protein targets for structure-based anti-Mycobacterium tuberculosis drug discovery

Review

Abstract

Mycobacterium tuberculosis, which belongs to the genus Mycobacterium, is the pathogenic agent for most tuberculosis (TB). As TB remains one of the most rampant infectious diseases, causing morbidity and death with emergence of multi-drug-resistant and extensively-drug-resistant forms, it is urgent to identify new drugs with novel targets to ensure future therapeutic success. In this regards, the structural genomics of M. tuberculosis provides important information to identify potential targets, perform biochemical assays, determine crystal structures in complex with potential inhibitor(s), reveal the key sites/residues for biological activity, and thus validate drug targets and discover novel drugs. In this review, we will discuss the recent progress on novel targets for structure-based anti-M. tuberculosis drug discovery.

Keywords

Mycobacterium tuberculosis crystal structure drug discovery target 

References

  1. Andries, K., Verhasselt, P., Guillemont, J., Gohlmann, H.W., Neefs, J. M., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., et al. (2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223–227.CrossRefGoogle Scholar
  2. Bhatt, A., Molle, V., Besra, G.S., Jacobs, W.R., Jr., and Kremer, L. (2007). The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development. Mol Microbiol 64, 1442–1454.CrossRefGoogle Scholar
  3. Bocchino, M., Sanduzzi, A., and Bariffi, F. (2000). Mycobacterium tuberculosis and HIV co-infection in the lung: synergic immune dysregulation leading to disease progression. Monaldi Arch Chest Dis 55, 381–388.Google Scholar
  4. Brunger, A.T., Adams, P.D., Clore, G.M., DeLano, W.L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.S., Kuszewski, J., Nilges, M., Pannu, N.S., et al. (1998). Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta Crystallogr D Biol Crystallogr 54, 905–921.CrossRefGoogle Scholar
  5. Carroll, P., Pashley, C.A., and Parish, T. (2008). Functional analysis of GlnE, an essential adenylyl transferase in Mycobacterium tuberculosis. J Bacteriol 190, 4894–4902.CrossRefGoogle Scholar
  6. Chatterjee, D. (1997). The mycobacterial cell wall: structure, biosynthesis and sites of drug action. Curr Opin Chem Biol 1, 579–588.CrossRefGoogle Scholar
  7. Chaudhuri, B.N., Sawaya, M.R., Kim, C.Y., Waldo, G.S., Park, M.S., Terwilliger, T.C., and Yeates, T.O. (2003). The crystal structure of the first enzyme in the pantothenate biosynthetic pathway, ketopantoate hydroxymethyltransferase, from M tuberculosis. Structure 11, 753–764.CrossRefGoogle Scholar
  8. Chetnani, B., Das, S., Kumar, P., Surolia, A., and Vijayan, M. (2009). Mycobacterium tuberculosis pantothenate kinase: possible changes in location of ligands during enzyme action. Acta Crystallogr D Biol Crystallogr 65, 312–325.CrossRefGoogle Scholar
  9. Cohen-Gonsaud, M., Ducasse, S., Hoh, F., Zerbib, D., Labesse, G., and Quemard, A. (2002). Crystal structure of MabA from Mycobacterium tuberculosis, a reductase involved in long-chain fatty acid biosynthesis. J Mol Biol 320, 249–261.CrossRefGoogle Scholar
  10. Cole, S.T., Eiglmeier, K., Parkhill, J., James, K.D., Thomson, N.R., Wheeler, P.R., Honore, N., Garnier, T., Churcher, C., Harris, D., et al. (2001). Massive gene decay in the leprosy bacillus. Nature 409, 1007–1011.CrossRefGoogle Scholar
  11. Deckers-Hebestreit, G., and Altendorf, K. (1996). The F0F1-type ATP synthases of bacteria: structure and function of the F0 complex. Annu Rev Microbiol 50, 791–824.CrossRefGoogle Scholar
  12. Dessen, A., Quemard, A., Blanchard, J.S., Jacobs, W.R., Jr., and Sacchettini, J.C. (1995). Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science 267, 1638–1641.CrossRefGoogle Scholar
  13. Dias, M.V., Borges, J.C., Ely, F., Pereira, J.H., Canduri, F., Ramos, C. H., Frazzon, J., Palma, M.S., Basso, L.A., Santos, D.S., et al. (2006). Structure of chorismate synthase from Mycobacterium tuberculosis. J Struct Biol 154, 130–143.CrossRefGoogle Scholar
  14. Ducasse-Cabanot, S., Cohen-Gonsaud, M., Marrakchi, H., Nguyen, M., Zerbib, D., Bernadou, J., Daffe, M., Labesse, G., and Quemard, A. (2004). In vitro inhibition of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA by isoniazid. Antimicrob Agents Chemother 48, 242–249.CrossRefGoogle Scholar
  15. Feng, Z., and Barletta, R.G. (2003). Roles of Mycobacterium smegmatis D-alanine:D-alanine ligase and D-alanine racemase in the mechanisms of action of and resistance to the peptidoglycan inhibitor D-cycloserine. Antimicrob Agents Chemother 47, 283–291.CrossRefGoogle Scholar
  16. Fioravanti, E., Adam, V., Munier-Lehmann, H., and Bourgeois, D. (2005). The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3′-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition. Biochemistry 44, 130–137.CrossRefGoogle Scholar
  17. Fioravanti, E., Haouz, A., Ursby, T., Munier-Lehmann, H., Delarue, M., and Bourgeois, D. (2003). Mycobacterium tuberculosis thymidylate kinase: structural studies of intermediates along the reaction pathway. J Mol Biol 327, 1077–1092.CrossRefGoogle Scholar
  18. Fontecave, M., Nordlund, P., Eklund, H., and Reichard, P. (1992). The redox centers of ribonucleotide reductase of Escherichia coli. Adv Enzymol Relat Areas Mol Biol 65, 147–183.Google Scholar
  19. Georgieva, E.R., Narvaez, A.J., Hedin, N., and Graslund, A. (2008). Secondary structure conversions of Mycobacterium tuberculosis ribonucleotide reductase protein R2 under varying pH and temperature conditions. Biophys Chem 137, 43–48.CrossRefGoogle Scholar
  20. Godreuil, S., Renaud, F., Van de Perre, P., Carriere, C., Torrea, G., and Banuls, A.L. (2007). Genetic diversity and population structure of Mycobacterium tuberculosis in HIV-1-infected compared with uninfected individuals in Burkina Faso. Aids 21, 248–250.CrossRefGoogle Scholar
  21. Gong, C., Martins, A., Bongiorno, P., Glickman, M., and Shuman, S. (2004). Biochemical and genetic analysis of the four DNA ligases of mycobacteria. J Biol Chem 279, 20594–20606.CrossRefGoogle Scholar
  22. Gould, T.A., van de Langemheen, H., Munoz-Elias, E.J., McKinney, J. D., and Sacchettini, J.C. (2006). Dual role of isocitrate lyase 1 in the glyoxylate and methylcitrate cycles in Mycobacterium tuberculosis. Mol Microbiol 61, 940–947.CrossRefGoogle Scholar
  23. Gourley, D.G., Shrive, A.K., Polikarpov, I., Krell, T., Coggins, J.R., Hawkins, A.R., Isaacs, N.W., and Sawyer, L. (1999). The two types of 3-dehydroquinase have distinct structures but catalyze the same overall reaction. Nat Struct Biol 6, 521–525.CrossRefGoogle Scholar
  24. Haouz, A., Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Herdewijn, P., Van Calenbergh, S., and Delarue, M. (2003). Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism. J Biol Chem 278, 4963–4971.CrossRefGoogle Scholar
  25. Hasan, S., Daugelat, S., Rao, P.S., and Schreiber, M. (2006). Prioritizing genomic drug targets in pathogens: application to Mycobacterium tuberculosis. PLoS Comput Biol 2, e61.CrossRefGoogle Scholar
  26. He, X., and Reynolds, K.A. (2002). Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob Agents Chemother 46, 1310–1318.CrossRefGoogle Scholar
  27. Huang, H., Scherman, M.S., D’Haeze, W., Vereecke, D., Holsters, M., Crick, D.C., and McNeil, M.R. (2005). Identification and active expression of the Mycobacterium tuberculosis gene encoding 5-phospho-“alpha”-d-ribose-1-diphosphate: decaprenyl-phosphate 5-phosphoribosyltransferase, the first enzyme committed to decaprenylphosphoryl-d-arabinose synthesis. J Biol Chem 280, 24539–24543.CrossRefGoogle Scholar
  28. Jordan, A., Pontis, E., Aslund, F., Hellman, U., Gibert, I., and Reichard, P. (1996). The ribonucleotide reductase system of Lactococcus lactis. Characterization of an NrdEF enzyme and a new electron transport protein. J Biol Chem 271, 8779–8785.CrossRefGoogle Scholar
  29. Kremer, L., Dover, L.G., Morehouse, C., Hitchin, P., Everett, M., Morris, H.R., Dell, A., Brennan, P.J., McNeil, M.R., Flaherty, C., et al. (2001). Galactan biosynthesis in Mycobacterium tuberculosis. Identification of a bifunctional UDP-galactofuranosyltransferase. J Biol Chem 276, 26430–26440.CrossRefGoogle Scholar
  30. Kurth, D.G., Gago, G.M., de la Iglesia, A., Bazet Lyonnet, B., Lin, T. W., Morbidoni, H.R., Tsai, S.C., and Gramajo, H. (2009). ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiology 155, 2664–2675.CrossRefGoogle Scholar
  31. Lederer, E., Adam, A., Ciorbaru, R., Petit, J.F., and Wietzerbin, J. (1975). Cell walls of Mycobacteria and related organisms; chemistry and immunostimulant properties. Mol Cell Biochem 7, 87–104.CrossRefGoogle Scholar
  32. Leger, M., Gavalda, S., Guillet, V., van der Rest, B., Slama, N., Montrozier, H., Mourey, L., Quemard, A., Daffe, M., and Marrakchi, H. (2009). The dual function of the Mycobacterium tuberculosis FadD32 required for mycolic acid biosynthesis. Chem Biol 16, 510–519.CrossRefGoogle Scholar
  33. LeMagueres, P., Im, H., Ebalunode, J., Strych, U., Benedik, M.J., Briggs, J.M., Kohn, H., and Krause, K.L. (2005). The 1.9 Å crystal structure of alanine racemase from Mycobacterium tuberculosis contains a conserved entryway into the active site. Biochemistry 44, 1471–1481.CrossRefGoogle Scholar
  34. Li de la Sierra, I., Munier-Lehmann, H., Gilles, A.M., Barzu, O., and Delarue, M. (2001). X-ray structure of TMP kinase from Mycobacterium tuberculosis complexed with TMP at 1.95 Å resolution. J Mol Biol 311, 87–100.CrossRefGoogle Scholar
  35. Li, W., Xin, Y., McNeil, M.R., and Ma, Y. (2006). rmlB and rmlC genes are essential for growth of mycobacteria. Biochem Biophys Res Commun 342, 170–178.CrossRefGoogle Scholar
  36. Ma, Y., Stern, R.J., Scherman, M.S., Vissa, V.D., Yan, W., Jones, V.C., Zhang, F., Franzblau, S.G., Lewis, W.H., and McNeil, M.R. (2001). Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob Agents Chemother 45, 1407–1416.CrossRefGoogle Scholar
  37. Maier, T., Jenni, S., and Ban, N. (2006). Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science 311, 1258–1262.CrossRefGoogle Scholar
  38. Marques, M.A., Neves-Ferreira, A.G., da Silveira, E.K., Valente, R.H., Chapeaurouge, A., Perales, J., da Silva Bernardes, R., Dobos, K. M., Spencer, J.S., Brennan, P.J., et al. (2008). Deciphering the proteomic profile of Mycobacterium leprae cell envelope. Proteomics 8, 2477–2491.CrossRefGoogle Scholar
  39. McCoy, A.J., Grosse-Kunstleve, R.W., Adams, P.D., Winn, M.D., Storoni, L.C., and Read, R.J. (2007). Phaser crystallographic software. J Appl Crystallogr 40, 658–674.CrossRefGoogle Scholar
  40. Mdluli, K., and Spigelman, M. (2006). Novel targets for tuberculosis drug discovery. Curr Opin Pharmacol 6, 459–467.CrossRefGoogle Scholar
  41. Meganathan, R. (2001). Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q): a perspective on enzymatic mechanisms. Vitam Horm 61, 173–218.CrossRefGoogle Scholar
  42. Mowa, M.B., Warner, D.F., Kaplan, G., Kana, B.D., and Mizrahi, V. (2009). Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria. J Bacteriol 191, 985–995.CrossRefGoogle Scholar
  43. Munoz-Elias, E.J., and McKinney, J.D. (2005). Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat Med 11, 638–644.CrossRefGoogle Scholar
  44. Munoz-Elias, E.J., Upton, A.M., Cherian, J., and McKinney, J.D. (2006). Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Mol Microbiol 60, 1109–1122.CrossRefGoogle Scholar
  45. Musayev, F., Sachdeva, S., Scarsdale, J.N., Reynolds, K.A., and Wright, H.T. (2005). Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A. J Mol Biol 346, 1313–1321.CrossRefGoogle Scholar
  46. Nakano, Y., Suzuki, N., Yoshida, Y., Nezu, T., Yamashita, Y., and Koga, T. (2000). Thymidine diphosphate-6-deoxy-L-lyxo-4-hexulose reductase synthesizing dTDP-6-deoxy-L-talose from Actinobacillus actinomycetemcomitans. J Biol Chem 275, 6806–6812.CrossRefGoogle Scholar
  47. Nunn, C.M., Djordjevic, S., Hillas, P.J., Nishida, C.R., and Ortiz de Montellano, P.R. (2002). The crystal structure of Mycobacterium tuberculosis alkylhydroperoxidase AhpD, a potential target for antitubercular drug design. J Biol Chem 277, 20033–20040.CrossRefGoogle Scholar
  48. Oliveira, J.S., Pereira, J.H., Canduri, F., Rodrigues, N.C., de Souza, O.N., de Azevedo, W.F., Jr., Basso, L.A., and Santos, D.S. (2006). Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP (CoA) reductase enzymes from Mycobacterium tuberculosis. J Mol Biol 359, 646–666.CrossRefGoogle Scholar
  49. Portevin, D., de Sousa-D’Auria, C., Montrozier, H., Houssin, C., Stella, A., Laneelle, M.A., Bardou, F., Guilhot, C., and Daffe, M. (2005). The acyl-AMP ligase FadD32 and AccD4-containing acyl-CoA carboxylase are required for the synthesis of mycolic acids and essential for mycobacterial growth: identification of the carboxylation product and determination of the acyl-CoA carboxylase components. J Biol Chem 280, 8862–8874.CrossRefGoogle Scholar
  50. Qureshi, H., Arif, A., Alam, E., and Qadir, N. (2010). Integration of informal medical practitioners in DOTS implementation to improve case detection rate. J Pak Med Assoc 60, 33–37.Google Scholar
  51. Raman, K., Rajagopalan, P., and Chandra, N. (2005). Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs. PLoS Comput Biol 1, e46.CrossRefGoogle Scholar
  52. Rivers, E.C., and Mancera, R.L. (2008a). New anti-tuberculosis drugs in clinical trials with novel mechanisms of action. Drug Discov Today 13, 1090–1098.CrossRefGoogle Scholar
  53. Rivers, E.C., and Mancera, R.L. (2008b). New anti-tuberculosis drugs with novel mechanisms of action. Curr Med Chem 15, 1956–1967.CrossRefGoogle Scholar
  54. Rodriguez-Concepcion, M. (2004). The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs. Curr Pharm Des 10, 2391–2400.CrossRefGoogle Scholar
  55. Sambandamurthy, V.K., Wang, X., Chen, B., Russell, R.G., Derrick, S., Collins, F.M., Morris, S.L., and Jacobs, W.R., Jr. (2002). A pantothenate auxotroph of Mycobacterium tuberculosis is highly attenuated and protects mice against tuberculosis. Nat Med 8, 1171–1174.CrossRefGoogle Scholar
  56. Scarsdale, J.N., Kazanina, G., He, X., Reynolds, K.A., and Wright, H. T. (2001). Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III. J Biol Chem 276, 20516–20522.CrossRefGoogle Scholar
  57. Sharma, V., Grubmeyer, C., and Sacchettini, J.C. (1998). Crystal structure of quinolinic acid phosphoribosyltransferase from Mmycobacterium tuberculosis: a potential TB drug target. Structure 6, 1587–1599.CrossRefGoogle Scholar
  58. Sharma, V., Sharma, S., Hoener zu Bentrup, K., McKinney, J.D., Russell, D.G., Jacobs, W.R., Jr., and Sacchettini, J.C. (2000). Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nat Struct Biol 7, 663–668.CrossRefGoogle Scholar
  59. Sjoberg, B.M., Reichard, P., Graslund, A., and Ehrenberg, A. (1978). The tyrosine free radical in ribonucleotide reductase from Escherichia coli. J Biol Chem 253, 6863–6865.Google Scholar
  60. Srivastava, S.K., Dube, D., Kukshal, V., Jha, A.K., Hajela, K., and Ramachandran, R. (2007). NAD+-dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: novel structurefunction relationship and identification of a specific inhibitor. Proteins 69, 97–111.CrossRefGoogle Scholar
  61. Srivastava, S.K., Tripathi, R.P., and Ramachandran, R. (2005). NAD+-dependent DNA Ligase (Rv3014c) from Mycobacterium tuberculosis. Crystal structure of the adenylation domain and identification of novel inhibitors. J Biol Chem 280, 30273–30281.CrossRefGoogle Scholar
  62. Takayama, K., Wang, C., and Besra, G.S. (2005). Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev 18, 81–101.CrossRefGoogle Scholar
  63. Tang, Y., Kim, C.Y., Mathews, II, Cane, D.E., and Khosla, C. (2006). The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc Natl Acad Sci U S A 103, 11124–11129.CrossRefGoogle Scholar
  64. Teh, J.S., Yano, T., and Rubin, H. (2007). Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets 7, 169–181.CrossRefGoogle Scholar
  65. Trivedi, O.A., Arora, P., Sridharan, V., Tickoo, R., Mohanty, D., and Gokhale, R.S. (2004). Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature 428, 441–445.CrossRefGoogle Scholar
  66. Uppsten, M., Davis, J., Rubin, H., and Uhlin, U. (2004). Crystal structure of the biologically active form of class Ib ribonucleotide reductase small subunit from Mycobacterium tuberculosis. FEBS Lett 569, 117–122.CrossRefGoogle Scholar
  67. Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Busson, R., Rozenski, J., Herdewijn, P., and Van Calenbergh, S. (2004). Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem 47, 6187–6194.CrossRefGoogle Scholar
  68. Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Dugue, L., Heyerick, A., De Keukeleire, D., Pochet, S., Busson, R., Herdewijn, P., and Van Calenbergh, S. (2003). 3′-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. J Med Chem 46, 3811–3821.CrossRefGoogle Scholar
  69. Visca, P., Fabozzi, G., Milani, M., Bolognesi, M., and Ascenzi, P. (2002). Nitric oxide and Mycobacterium leprae pathogenicity. IUBMB Life 54, 95–99.CrossRefGoogle Scholar
  70. Vispe, S., and Satoh, M.S. (2000). DNA repair patch-mediated double strand DNA break formation in human cells. J Biol Chem 275, 27386–27392.Google Scholar
  71. Wang, S., and Eisenberg, D. (2003). Crystal structures of a pantothenate synthetase from M. tuberculosis and its complexes with substrates and a reaction intermediate. Protein Sci 12, 1097–1108.CrossRefGoogle Scholar
  72. Wang, S., and Eisenberg, D. (2006). Crystal structure of the pantothenate synthetase from Mycobacterium tuberculosis, snapshots of the enzyme in action. Biochemistry 45, 1554–1561.CrossRefGoogle Scholar
  73. Weinstein, E.A., Yano, T., Li, L.S., Avarbock, D., Avarbock, A., Helm, D., McColm, A.A., Duncan, K., Lonsdale, J.T., and Rubin, H. (2005). Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A 102, 4548–4553.CrossRefGoogle Scholar
  74. Yano, T., Li, L.S., Weinstein, E., Teh, J.S., and Rubin, H. (2006). Steady-state kinetics and inhibitory action of antitubercular phenothiazines on mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2). J Biol Chem 281, 11456–11463.CrossRefGoogle Scholar
  75. Yuan, Y., Crane, D.C., Musser, J.M., Sreevatsan, S., and Barry, C.E., 3rd (1997). MMAS-1, the branch point between cis- and transcyclopropane-containing oxygenated mycolates in Mycobacterium tuberculosis. J Biol Chem 272, 10041–10049.CrossRefGoogle Scholar
  76. Zhou, X., Lou, Z., Fu, S., Yang, A., Shen, H., Li, Z., Feng, Y., Bartlam, M., Wang, H., and Rao, Z. Crystal structure of ArgP from Mycobacterium tuberculosis confirms two distinct conformations of full-length LysR transcriptional regulators and reveals its function in DNA binding and transcriptional regulation. J Mol Biol 396, 1012–1024.Google Scholar

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© Higher Education Press and Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Laboratory of Structural BiologyTsinghua UniversityBeijingChina
  2. 2.Higher Education PressBeijingChina

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